0%
CTNNB1c.2175C>TUncertain significance
Print report
Variant interpretation report

CTNNB1 c.2175C>T, p.Gly725=

NM_001904.4:c.2175C>T NP_001895.1:p.(Gly725=) Synonymous · exon 15 View identifiers
Classification
Uncertain significance

Variant description:

The CTNNB1 NM_001904.4:c.2175C>T (NP_001895.1:p.(Gly725=)) synonymous variant has previously been reported in somatic cancers (COSMIC; COSV62710594, n = 1 time). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CTNNB1

CTNNB1 encodes beta-catenin, a protein with dual roles in cell adhesion and gene regulation. It is part of the adherens junctions that maintain epithelial cell layers by controlling cell growth and cell-cell adhesion, and it also anchors the actin cytoskeleton and helps transmit the signal that stops cells from dividing once a tissue layer is complete. In the WNT signaling pathway, beta-catenin acts as a transcriptional activator that switches on growth-related genes such as Cyclin D1 and MYC. The gene is associated with colorectal cancer, pilomatrixoma, medulloblastoma, and ovarian cancer, and it acts as an oncogene: excessive beta-catenin activity is common in many solid tumors, including uterine, ovarian, liver, and colorectal cancers.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v4.1 AF 6.44351e-05 is below the generic PM2 supporting threshold of <=0.0001, with zero homozygotes.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM2 (supporting) is the only applied criterion and does not satisfy a generic ACMG/AMP pathogenic or benign combination rule.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
104 / 1,614,028 alleles

gnomAD v4.1: 104 / 1,614,028 alleles. Recorded AF 6.44351e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.83152e-05; MAF= 0.00283%, 8/282534 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277162; MAF= 0.02772%, 2/7216 alleles, homozygotes = 0); grpmax FAF= 2.24e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
2 reported laboratory submissions

2 Likely benign. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV62710594, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 7 not met · 11 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

None of PS2, PM6, PP1, or BS4 can be assessed because the available evidence does not document proband phenotype, parental testing, family history, affected relatives, or segregation results.

No VCEP covers CTNNB1 in this case, so the supplied generic ACMG/AMP 2015 definitions govern.

The exact variant is synonymous, NM_001904.4:c.2175C>T (NP_001895.1:p.(Gly725=)).

The literature packet contains no ai_classified_papers and no variant-specific case-control, phenotype-specific, alternate-molecular-basis, or qualifying expert-panel evidence for these five criteria.

ClinVar evidence is limited to two exact-variant clinical-laboratory Likely benign submissions with zero expert-panel submissions; ordinary laboratory submissions and aggregate labels do not trigger PP5 or BP6.

The variant is synonymous, so PP3 and BP4 use only the SpliceAI path and BP7 requires both no predicted splice impact and low conservation.

SpliceAI returned no score because the query timed out; this missing result is not evidence of no splice impact.

Population evidence supports PM2 at supporting strength because the variant remains below the supplied 0.0001 threshold in the default all-comers gnomAD datasets and in the non-cancer subsets.

BA1 and BS1 are not met because the observed frequencies are far below 0.05 and 0.01, respectively.

BS2 is not assessed because the population records do not provide an individual-level healthy adult observation with documented age, zygosity, phenotype, and penetrance context.

Met · 1

PM2 SupportingACMGMet at supporting: gnomAD v4.1 AF 6.44351e-05 is below the generic PM2 supporting threshold of <=0.0001, with zero homozygotes. Details ▾Hide ▴
Reasoning

PM2 is met at supporting strength. Under the generic default, the variant is present only at an extremely low frequency in gnomAD v4.1 all-comers (6.44351e-05; 104/1,614,028 alleles; zero homozygotes), below the supplied <=0.0001 PM2 supporting threshold. The result is concordant in gnomAD v2.1 all-comers (2.83152e-05), gnomAD v2.1 non-cancer exomes (2.53599e-05), and gnomAD v3.1 non-cancer genomes (4.05575e-05), all with zero homozygotes.

Rule
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Evidence considered
  • gnomAD v4.1 all-comers: AF=6.44351e-05 (104/1,614,028 alleles), homozygotes=0; maximum reported population AF=9.60184e-05, still below 0.0001.
  • gnomAD v2.1 all-comers: AF=2.83152e-05 (8/282,534 alleles), homozygotes=0.
  • gnomAD v2.1 non-cancer exomes: AF=2.53599e-05 (6/236,594 alleles), homozygotes=0; gnomAD v3.1 non-cancer genomes: AF=4.05575e-05 (6/147,938 alleles), homozygotes=0.
  • Applied the supplied generic PM2 supporting threshold of <=0.0001, identified as the ClinGen SVI recommendation to downgrade PM2 to supporting (PMID:25741868), because the governing framework is generic ACMG/AMP rather than a VCEP specification.
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗

Not met · 7 · evaluated, threshold not reached

PS4 ACMG_2015Not met: no affected-versus-control counts, matched-ancestry frequency comparison, odds ratio, or confidence interval was available for the exact variant. Details ▾Hide ▴
Reasoning

No qualifying case-control comparison was identified for NM_001904.4:c.2175C>T (NP_001895.1:p.(Gly725=)). The literature_pass.json packet has no ai_classified_papers, and its two cited papers were not variant-specific case-control studies. No affected-case count paired with unaffected or population-control count, matched-ancestry frequency comparison, OR/RR, or 95% CI was available. Therefore the ACMG/AMP PS4 requirement is not met; no numeric PS4 comparison can be calculated.

Rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
Evidence considered
  • literature_pass.json: ai_classified_papers is empty; no paper was preclassified as PS4.
  • PMID:25741868 paper_extracts finding: the paper does not mention CTNNB1 or c.2175C>T and reports no variant-specific clinical or population findings.
  • ClinVar exact-variant record identifies two non-expert-panel clinical-laboratory Likely benign submissions, not a case-control study.
  • gnomAD v2.1 reports 8/282534 alleles (AF 2.83152e-05); gnomAD v4.1 reports 104/1614028 alleles (AF 6.44351e-05), but no affected-case frequency is available, so an OR/RR and 95% CI cannot be calculated.
Still missing
  • A case-control study or affected-case and matched-control/population counts with which to calculate OR/RR and its 95% CI.
Sources
PMID:25741868 ↗clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 ACMG_2015Not met: the synonymous variant's required SpliceAI max delta is unavailable, so it cannot reach the PP3 supporting threshold of >=0.2. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_001904.4:c.2175C>T; NP_001895.1:p.(Gly725=)), so the generic PP3 splice path applies and requires SpliceAI. SpliceAI returned no score (max delta unavailable because the query timed out), so the applicable computational evidence is indeterminate and PP3 is not met. Pangolin scores (SG 0.008; SL -0.03) are not used because Pangolin is not a calibrated predictor for this generic PP3/BP4 decision. The supplied SpliceAI thresholds are PP3 supporting >=0.2 and moderate >=0.5 (Jaganathan et al. 2019, PMID:30661751).

Rule
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Evidence considered
  • Variant consequence: synonymous, NM_001904.4:c.2175C>T, NP_001895.1:p.(Gly725=).
  • SpliceAI returned no scores; max delta is null because the read operation timed out. This is missing data, not evidence of no splice impact.
  • Pangolin SG 0.008 and SL -0.03 were not used because Pangolin is not calibrated for generic PP3/BP4 here.
  • Generic SpliceAI calibration: PP3 supporting >=0.2 and moderate >=0.5, Jaganathan et al. 2019 (PMID:30661751).
Still missing
  • A valid SpliceAI max delta score is unavailable; no calibrated splice predictor result can be assessed for PP3.
Sources
spliceai ↗
PP5 ACMG_2015Not met: ClinVar has zero expert-panel submissions and the two exact-variant laboratory submissions classify it as Likely benign, not pathogenic. Details ▾Hide ▴
Reasoning

The exact variant has two clinical-laboratory Likely benign ClinVar submissions, with zero expert-panel submissions. No reputable source reporting this exact variant as pathogenic was identified, so PP5 is not met.

Rule
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
  • ClinVar exact match NM_001904.4(CTNNB1):c.2175C>T (p.Gly725=): two clinical-laboratory Likely benign submissions and expert_panel_submissions = 0.
  • The cited ClinVar PMID trails are PMID:28492532 and PMID:25741868; neither is an exact-variant expert-panel pathogenic classification, and PMID:25741868 paper_extracts states that the variant is not mentioned.
Sources
clinvar ↗PMID:25741868 ↗
BA1 ACMG_2015Not met: gnomAD v4.1 all-comers AF 6.44351e-05 is far below the BA1 threshold of 0.05. Details ▾Hide ▴
Reasoning

BA1 is not met. The highest relevant all-comers allele frequency is 6.44351e-05 in gnomAD v4.1 (104/1,614,028 alleles), far below the 0.05 stand-alone threshold; gnomAD v2.1 all-comers AF was 2.83152e-05 (8/282,534), and the non-cancer datasets were also far below 5% (v2.1 exomes 2.53599e-05; v3.1 genomes 4.05575e-05).

Rule
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Evidence considered
  • gnomAD v4.1 all-comers: 104/1,614,028 alleles, AF=6.44351e-05, homozygotes=0; maximum reported population AF was 9.60184e-05 in Remaining individuals.
  • gnomAD v2.1 all-comers: 8/282,534 alleles, AF=2.83152e-05, homozygotes=0.
  • The non-cancer subsets were concordant: gnomAD v2.1 non-cancer exomes AF=2.53599e-05 (6/236,594), and gnomAD v3.1 non-cancer genomes AF=4.05575e-05 (6/147,938), both with zero homozygotes.
  • Applied the published generic BA1 stand-alone threshold of >=0.05 from ACMG/AMP 2015 (PMID:25741868), as supplied for this case.
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
BS1 ACMG_2015Not met: the maximum observed AF is 6.44351e-05, well below the generic BS1 default of 0.01 for this early-onset dominant disorder. Details ▾Hide ▴
Reasoning

BS1 is not met. The observed frequency is 6.44351e-05 in gnomAD v4.1 all-comers and 2.83152e-05 in gnomAD v2.1, with non-cancer frequencies of 2.53599e-05 (v2.1 exomes) and 4.05575e-05 (v3.1 genomes), all well below the generic 0.01 default. CTNNB1-related neurodevelopmental disease is an early-onset, apparently highly penetrant dominant disorder in the supplied case context, so no reduced-penetrance or founder-ancestry exception is indicated and no maximum-credible-frequency calculation is needed to reject BS1 here.

Rule
Allele frequency is greater than expected for the disorder.
Evidence considered
  • gnomAD v4.1 all-comers: AF=6.44351e-05 (104/1,614,028 alleles), with maximum reported population AF=9.60184e-05; no homozygotes.
  • gnomAD v2.1 all-comers: AF=2.83152e-05 (8/282,534 alleles); non-cancer exomes AF=2.53599e-05 (6/236,594).
  • gnomAD v3.1 non-cancer genomes: AF=4.05575e-05 (6/147,938), with maximum reported population AF=6.1717e-05; no homozygotes.
  • The case evidence describes CTNNB1-related neurodevelopmental disease as presenting early in life and as a heterozygous germline disorder; no evidence was supplied for reduced penetrance, late onset, or a founder allele that would make this frequency compatible with pathogenicity.
  • Applied the supplied generic BS1 default threshold of >=0.01, with maximum-credible-frequency considerations from Whiffin et al. 2017 (PMID:28518168).
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
BP4 ACMG_2015Not met: the synonymous variant's required SpliceAI max delta is unavailable, so no result can be shown to meet the BP4 threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_001904.4:c.2175C>T; NP_001895.1:p.(Gly725=)), so the generic BP4 splice path applies and requires SpliceAI. SpliceAI returned no score (max delta unavailable because the query timed out), so the applicable computational evidence is indeterminate and BP4 is not met. The absence of a SpliceAI result cannot be treated as a low score, and the Pangolin scores (SG 0.008; SL -0.03) are not substituted because Pangolin is not a calibrated predictor for this generic PP3/BP4 decision. The supplied SpliceAI BP4 threshold is max delta <=0.1 (Jaganathan et al. 2019, PMID:30661751).

Rule
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Evidence considered
  • Variant consequence: synonymous, NM_001904.4:c.2175C>T, NP_001895.1:p.(Gly725=).
  • SpliceAI returned no scores; max delta is null because the read operation timed out. This is missing data, not evidence of absent splice impact.
  • Pangolin SG 0.008 and SL -0.03 were not used because Pangolin is not calibrated for generic PP3/BP4 here.
  • Generic SpliceAI calibration: BP4 supporting requires max delta <=0.1, Jaganathan et al. 2019 (PMID:30661751).
Still missing
  • A valid SpliceAI max delta score is unavailable; no calibrated splice predictor result can be assessed for BP4.
Sources
spliceai ↗
BP6 ACMG_2015Not met: ClinVar reports Likely benign from two clinical laboratories but zero expert-panel submissions, so no qualifying reputable-source benign report is available. Details ▾Hide ▴
Reasoning

The exact variant is classified Likely benign by two clinical laboratories in ClinVar, but the record has zero expert-panel submissions. Under the required rule, no qualifying reputable-source benign report is available for BP6, so it is not met.

Rule
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
  • ClinVar exact match NM_001904.4(CTNNB1):c.2175C>T (p.Gly725=): two clinical-laboratory Likely benign submissions; expert_panel_submissions = 0.
  • The two submissions are ordinary clinical-laboratory assertions, not expert-panel classifications, and therefore cannot trigger BP6 under the required generic rule.
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 ACMG_2015Not assessed: parental maternity and paternity confirmation, family history, and proband disease documentation are unavailable. Details ▾Hide ▴
Reasoning

No proband-level clinical report, family history, or parental testing result is available for NM_001904.4:c.2175C>T; therefore confirmed de novo status and disease consistency cannot be assessed.

Rule
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Evidence considered
  • The available case evidence contains no proband-level phenotype, family-history, maternity, or paternity-testing data for NM_001904.4:c.2175C>T.
  • The variant is annotated as NM_001904.4:c.2175C>T (NP_001895.1:p.(Gly725=)), but variant annotation does not establish de novo occurrence or disease status.
Still missing
  • Proband diagnosis and phenotype consistency are not documented.
  • Family history is not documented.
  • Both maternity and paternity are not confirmed by parental testing.
PS3 ACMG_2015Not assessed: no variant-specific functional assay or validated damaging-effect measurement was available for CTNNB1 c.2175C>T (p.Gly725=). Details ▾Hide ▴
Reasoning

No variant-specific, well-established in vitro or in vivo functional study was identified for CTNNB1 c.2175C>T (p.Gly725=). The supplied literature consists of a general ACMG/AMP standards paper and a background review, with no assay result, experimental controls, biological-effect measurement, or validated reproducibility evidence for this synonymous variant. Therefore, the evidence is insufficient to assess PS3 rather than supporting a damaging effect.

Rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Evidence considered
  • No variant-specific in vitro or in vivo functional assay, assay-control result, biological-effect measurement, or reproducibility evidence for CTNNB1 c.2175C>T (p.Gly725=) was identified in the supplied evidence.
  • PMID:25741868 is a general ACMG/AMP standards paper; its extracted finding states that it contains no CTNNB1-specific functional or other variant-specific findings for this variant.
Still missing
  • A variant-specific in vitro or in vivo assay with appropriate controls, biological relevance, and reproducible evidence of a damaging effect is needed.
Sources
PMID:25741868 ↗PMID:28492532 ↗
PM6 ACMG_2015Not assessed: no documented de novo observation exists, and parental testing or maternity/paternity information is unavailable. Details ▾Hide ▴
Reasoning

No report establishes that NM_001904.4:c.2175C>T arose de novo in the proband, and no parental testing or maternity/paternity information is available; an assumed de novo event therefore cannot be assessed.

Rule
Assumed de novo, but without confirmation of paternity and maternity.
Evidence considered
  • The available case evidence contains no proband-parent genotype comparison or report of an assumed de novo occurrence for NM_001904.4:c.2175C>T.
  • No parental maternity or paternity information is provided.
Still missing
  • A proband-level de novo observation is not documented.
  • Parental testing status is not documented.
  • Maternity and paternity confirmation status is not documented.
PP1 ACMG_2015Not assessed: affected-relative genotypes, phenotype concordance, and the number of informative meioses are not documented. Details ▾Hide ▴
Reasoning

No affected relatives, family genotype data, phenotype concordance, or meiosis/segregation observations are documented for NM_001904.4:c.2175C>T; co-segregation cannot be assessed.

Rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Evidence considered
  • The available case evidence contains no pedigree, affected-relative testing, segregation table, or family-level phenotype information for NM_001904.4:c.2175C>T.
Still missing
  • No affected family members are documented.
  • No relatives' variant genotypes are documented.
  • No phenotype concordance or informative meioses are documented.
PP4 ACMG_2015Not assessed: no patient phenotype or family-history details were available to judge specificity for a single-gene disease. Details ▾Hide ▴
Reasoning

The available case evidence does not provide a patient phenotype or family history for this variant. Without phenotype details, specificity for a disease with a single genetic etiology cannot be judged under PP4.

Rule
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Evidence considered
  • The case evidence materials contain variant normalization and database findings but no patient phenotype or family-history description.
Still missing
  • Patient phenotype and family-history details, including the diagnosed disease and features supporting high specificity.
BS2 ACMG_2015Not assessed: gnomAD reports zero homozygotes but provides no individual-level healthy adult observation meeting the BS2 age, inheritance, and penetrance requirements. Details ▾Hide ▴
Reasoning

BS2 cannot be assessed from the available evidence. gnomAD v2.1 and v4.1 report zero homozygotes, but population allele counts do not identify a specific healthy adult heterozygote, establish adult age, or document absence of the early-onset CTNNB1-related phenotype; an individual-level healthy-adult observation is required.

Rule
BS2
Evidence considered
  • gnomAD v2.1 all-comers: 8/282,534 alleles with homozygotes=0; gnomAD v2.1 non-cancer exomes: 6/236,594 alleles with homozygotes=0.
  • gnomAD v4.1 all-comers: 104/1,614,028 alleles with homozygotes=0; the reported population-specific records also show homozygotes=0.
  • No source in the supplied population evidence identifies a specific healthy adult individual carrying this variant, and no hemizygous observation is relevant to this autosomal dominant CTNNB1 context.
Still missing
  • A documented healthy adult carrying the variant with ascertainable age, zygosity, phenotype, and the relevant CTNNB1 disease penetrance context is not available.
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
BS3 ACMG_2015Not assessed: no variant-specific functional assay or validated evidence showing no damaging effect on protein function or splicing was available. Details ▾Hide ▴
Reasoning

No variant-specific, well-established in vitro or in vivo functional study was identified for CTNNB1 c.2175C>T (p.Gly725=). The supplied literature consists of a general ACMG/AMP standards paper and a background review, with no assay result, experimental controls, biological-effect measurement, or validated reproducibility evidence showing no damaging effect on protein function or splicing. Therefore, the evidence is insufficient to assess BS3 rather than supporting a benign functional effect.

Rule
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Evidence considered
  • No variant-specific in vitro or in vivo functional assay, assay-control result, biological-effect measurement, or reproducibility evidence showing no damaging effect on CTNNB1 protein function or splicing was identified in the supplied evidence.
  • PMID:25741868 is a general ACMG/AMP standards paper; its extracted finding states that it contains no CTNNB1-specific functional or other variant-specific findings for this variant.
Still missing
  • A variant-specific in vitro or in vivo assay with appropriate controls, biological relevance, and reproducible evidence of no damaging effect on protein function or splicing is needed.
Sources
PMID:25741868 ↗PMID:28492532 ↗
BS4 ACMG_2015Not assessed: no affected relatives with documented absence of the variant are reported for evaluating non-segregation. Details ▾Hide ▴
Reasoning

No affected family members with documented negative testing for NM_001904.4:c.2175C>T are reported, so lack of segregation cannot be assessed and no conclusion about phenocopies or multiple pathogenic variants can be made.

Rule
Lack of segregation in affected members of a family.
Evidence considered
  • The available case evidence contains no affected-relative testing results or pedigree demonstrating non-segregation for NM_001904.4:c.2175C>T.
Still missing
  • Affected relatives are not documented.
  • Variant testing results for affected relatives are not documented.
  • Potential phenocopies and additional pathogenic variants cannot be evaluated.
BP2 ACMG_2015Not assessed: no pathogenic partner allele or parental, offspring, segregation, or molecular phase data establish cis or trans configuration. Details ▾Hide ▴
Reasoning

BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. The available case evidence contains no affected-proband-level observation establishing a pathogenic allele paired with NM_001904.4:c.2175C>T, and no parental, offspring, segregation, or molecular phase data establish either cis or trans phase. Accordingly, BP2 cannot be assessed.

Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
  • No affected-proband-level observation with a pathogenic partner variant was identified for NM_001904.4:c.2175C>T.
  • No parental, offspring, segregation, or molecular phase data were available to establish cis or trans configuration.
Still missing
  • Documented pathogenic variant paired with NM_001904.4:c.2175C>T in the same individual.
  • Parental, offspring, segregation, or molecular phasing results establishing cis or trans configuration.
BP5 ACMG_2015Not assessed: no patient record documents the exact variant together with an alternate molecular basis for the disease. Details ▾Hide ▴
Reasoning

No case report or clinical record in the available evidence documents this exact variant in a patient with an alternate molecular basis for disease. BP5 therefore cannot be assessed from the available case data.

Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
  • The available evidence contains no clinical case description, alternate pathogenic molecular finding, or paper reporting this exact variant in such a case.
Still missing
  • A case-level report showing the exact variant and an independent alternate molecular diagnosis explaining the phenotype.
BP7 ACMG_2015Not assessed: BP7 requires no splice impact and low conservation, but SpliceAI and qualifying conservation evidence are unavailable. Details ▾Hide ▴
Reasoning

The variant is synonymous, so BP7 is within scope. However, BP7 requires both a splice prediction showing no impact to the splice consensus sequence or creation of a new splice site and a finding that the nucleotide is not highly conserved. SpliceAI returned no score, and no qualifying conservation result is provided; therefore the required evidence is insufficient for assessment. Pangolin scores are not a substitute for the missing calibrated SpliceAI result.

Rule
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
  • Variant consequence: synonymous, NM_001904.4:c.2175C>T; BP7 is therefore applicable in principle.
  • SpliceAI returned no scores; max delta is null because the read operation timed out, so no no-impact splice conclusion can be made.
  • No qualifying conservation result for the nucleotide was provided.
  • Pangolin SG 0.008 and SL -0.03 were not used as a substitute for the required calibrated splice evidence.
Still missing
  • A valid splice prediction showing no splice impact is unavailable.
  • A qualifying assessment that the nucleotide is not highly conserved is unavailable.
Sources
spliceai ↗
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a synonymous variant. Details ▾Hide ▴
Reasoning

PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_null_variant_class
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PS1 N/ANot applicable: PS1 requires a missense variant, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules
PM1 N/ANot applicable: PM1 requires a missense variant, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules
PM3 N/ANot applicable: CTNNB1-related neurodevelopmental disorder is autosomal dominant, whereas PM3 is limited to recessive disorders with a confirmed pathogenic variant in trans. Details ▾Hide ▴
Reasoning

PM3 is restricted to recessive disorders and requires the tested variant to be detected in trans with a pathogenic variant, with phase established by parental or offspring testing. The supplied CTNNB1 disease evidence describes CTNNB1-related neurodevelopmental disorder as autosomal dominant, not recessive; therefore PM3 is not applicable to this gene-disease context. No trans pathogenic allele or parental phase observation is available for NM_001904.4:c.2175C>T.

Rule
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
Evidence considered
  • The supplied CTNNB1 disease-context evidence describes neurodevelopmental disorder with spastic diplegia and visual defects as an autosomal dominant syndrome.
  • No affected-proband observation, pathogenic allele in trans, or parental/offspring phase testing was identified for NM_001904.4:c.2175C>T.
PM4 N/ANot applicable: PM4 requires a protein-length change, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM5 N/ANot applicable: PM5 requires a missense variant, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules
PP2 N/ANot applicable: PP2 requires a missense variant, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules
BP1 N/ANot applicable: BP1 requires a missense variant, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules
BP3 N/ANot applicable: BP3 requires an in-frame indel in a repeat region, and this is a synonymous variant. Details ▾Hide ▴
Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001904.4:c.2175C>T in CTNNB1 is a synonymous (silent) substitution predicted to produce NP_001895.1:p.(Gly725=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for CTNNB1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules

Identifiers

Gene
CTNNB1
Transcript
NM_001904.4
Coding (HGVS c.)
NM_001904.4:c.2175C>T
Protein (HGVS p.)
NP_001895.1:p.(Gly725=)
GRCh38
chr3:41239171 C>T
GRCh37
chr3:41280662 C>T
Location and type
Exon 15 · synonymous
ClinVar
1917179, 1428947
COSMIC
COSV62710594

Gene diagram

Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001904.4. Select a row to find it on the plot.

CTNNB1NM_001904.4
Fetching transcript structure from UCSC…
gnomAD v4.1 104 / 1,614,028 alleles AF 6.44e-05 · 0 homozygotes · FAF 6.72e-05
gnomAD v2.1 8 / 282,534 alleles AF 2.83e-05 · 0 homozygotes · FAF 2.24e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.4e-05 · 104 / 1,614,028 alleles · 0 hom · FAF 6.7e-05
Remaining individuals6 / 62,488 9.6e-05
European (non-Finnish)95 / 1,180,016 8.1e-05
African/African American3 / 74,926 4e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 2.8e-05 · 8 / 282,534 alleles · 0 hom · FAF 2.2e-05
Remaining individuals2 / 7,216 0.00028
African/African American1 / 24,968 4e-05
European (non-Finnish)5 / 128,884 3.9e-05
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.44351e-05; MAF= 0.00644%, 104/1614028 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.60184e-05; MAF= 0.00960%, 6/62488 alleles, homozygotes = 0); grpmax FAF= 6.724e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.83152e-05; MAF= 0.00283%, 8/282534 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277162; MAF= 0.02772%, 2/7216 alleles, homozygotes = 0); grpmax FAF= 2.24e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.008

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 ACMG_2015Not met: the synonymous variant's required SpliceAI max delta is unavailable, so it cannot reach the PP3 supporting threshold of >=0.2. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_001904.4:c.2175C>T; NP_001895.1:p.(Gly725=)), so the generic PP3 splice path applies and requires SpliceAI. SpliceAI returned no score (max delta unavailable because the query timed out), so the applicable computational evidence is indeterminate and PP3 is not met. Pangolin scores (SG 0.008; SL -0.03) are not used because Pangolin is not a calibrated predictor for this generic PP3/BP4 decision. The supplied SpliceAI thresholds are PP3 supporting >=0.2 and moderate >=0.5 (Jaganathan et al. 2019, PMID:30661751).

Rule
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Evidence considered
  • Variant consequence: synonymous, NM_001904.4:c.2175C>T, NP_001895.1:p.(Gly725=).
  • SpliceAI returned no scores; max delta is null because the read operation timed out. This is missing data, not evidence of no splice impact.
  • Pangolin SG 0.008 and SL -0.03 were not used because Pangolin is not calibrated for generic PP3/BP4 here.
  • Generic SpliceAI calibration: PP3 supporting >=0.2 and moderate >=0.5, Jaganathan et al. 2019 (PMID:30661751).
Still missing
  • A valid SpliceAI max delta score is unavailable; no calibrated splice predictor result can be assessed for PP3.
Sources
spliceai ↗
BP4 ACMG_2015Not met: the synonymous variant's required SpliceAI max delta is unavailable, so no result can be shown to meet the BP4 threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_001904.4:c.2175C>T; NP_001895.1:p.(Gly725=)), so the generic BP4 splice path applies and requires SpliceAI. SpliceAI returned no score (max delta unavailable because the query timed out), so the applicable computational evidence is indeterminate and BP4 is not met. The absence of a SpliceAI result cannot be treated as a low score, and the Pangolin scores (SG 0.008; SL -0.03) are not substituted because Pangolin is not a calibrated predictor for this generic PP3/BP4 decision. The supplied SpliceAI BP4 threshold is max delta <=0.1 (Jaganathan et al. 2019, PMID:30661751).

Rule
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Evidence considered
  • Variant consequence: synonymous, NM_001904.4:c.2175C>T, NP_001895.1:p.(Gly725=).
  • SpliceAI returned no scores; max delta is null because the read operation timed out. This is missing data, not evidence of absent splice impact.
  • Pangolin SG 0.008 and SL -0.03 were not used because Pangolin is not calibrated for generic PP3/BP4 here.
  • Generic SpliceAI calibration: BP4 supporting requires max delta <=0.1, Jaganathan et al. 2019 (PMID:30661751).
Still missing
  • A valid SpliceAI max delta score is unavailable; no calibrated splice predictor result can be assessed for BP4.
Sources
spliceai ↗
BP7 ACMG_2015Not assessed: BP7 requires no splice impact and low conservation, but SpliceAI and qualifying conservation evidence are unavailable. Details ▾Hide ▴
Reasoning

The variant is synonymous, so BP7 is within scope. However, BP7 requires both a splice prediction showing no impact to the splice consensus sequence or creation of a new splice site and a finding that the nucleotide is not highly conserved. SpliceAI returned no score, and no qualifying conservation result is provided; therefore the required evidence is insufficient for assessment. Pangolin scores are not a substitute for the missing calibrated SpliceAI result.

Rule
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
  • Variant consequence: synonymous, NM_001904.4:c.2175C>T; BP7 is therefore applicable in principle.
  • SpliceAI returned no scores; max delta is null because the read operation timed out, so no no-impact splice conclusion can be made.
  • No qualifying conservation result for the nucleotide was provided.
  • Pangolin SG 0.008 and SL -0.03 were not used as a substitute for the required calibrated splice evidence.
Still missing
  • A valid splice prediction showing no splice impact is unavailable.
  • A qualifying assessment that the nucleotide is not highly conserved is unavailable.
Sources
spliceai ↗

Statement

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    The paper provides general ACMG/AMP standards but does not mention CTNNB1 or NM_001904.4:c.2175C>T and contains no variant-specific de novo, segregation, or non-segregation findings.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    Clinical reports should include sequence reference(s) to ensure unambiguous naming of the variant at the DNA level as well as provide coding and protein nomenclature to assist in functional interpretations (e.g., “g.” for genomic sequence, “c.” for coding DNA sequence, “p.” for protein, “m.” for mitochondria, etc.).

    Nomenclature

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 104 / 1,614,028 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar 2 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.44351e-05; MAF= 0.00644%, 104/1614028 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.60184e-05; MAF= 0.00960%, 6/62488 alleles, homozygotes = 0); grpmax FAF= 6.724e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.83152e-05; MAF= 0.00283%, 8/282534 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277162; MAF= 0.02772%, 2/7216 alleles, homozygotes = 0); grpmax FAF= 2.24e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 1428947)

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62710594, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.