NM_001904.4:c.643G>A

CTNNB1 · NP_001895.1:p.(Ala215Thr) · NM_001904.4

GRCh37: chr3:41266972 G>A · GRCh38: chr3:41225481 G>A

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Ala215Thr)

gnomAD AF

3.841821072760373e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is present at extremely low frequency in population databases (gnomAD v2.1: 4/282,282 alleles, AF=0.0014%; gnomAD v4.1: 62/1,613,818 alleles, AF=0.0038%; absent from gnomAD-Canada), meeting PM2 at supporting strength.

In silico predictors do not support a deleterious effect: REVEL score is 0.278, BayesDel is 0.13681, and SpliceAI predicts no splicing impact (max delta 0.02). However, these scores are insufficient to independently meet BP4.

This variant has been reported in ClinVar as Likely benign by one clinical laboratory (GeneDx) and as Uncertain significance by another (Labcorp/Invitae). No pathogenic classification has been asserted by any submitter.

No functional studies, segregation data, de novo observations, or variant-specific publications were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.

With only one supporting-level pathogenic criterion (PM2) met and no benign criteria met, the evidence is insufficient to classify this variant as either pathogenic or benign. This variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (p.Ala215Thr) that does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions under the ClinGen SVI PVS1 framework (PMC6185798).
PS1	Not met	No evidence of a different nucleotide change at this codon resulting in the same amino acid substitution (p.Ala215Thr) that has been established as pathogenic. The only ClinVar entries for this residue are for the identical variant c.643G>A, classified as Likely benign and Uncertain significance.	clinvar
PS2	Not met	No de novo observation was identified for this variant in any available source. No parental genotype data was available.
PS3	Not met	No well-established functional studies demonstrating a damaging effect were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific curated functional evidence. No publications with functional data for NM_001904.4:c.643G>A were retrieved.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals compared to controls. The variant is observed at extremely low frequency in gnomAD (4/282,282 in v2.1; 62/1,613,818 in v4.1) and has been reported in ClinVar by only two clinical laboratories without associated patient phenotype data.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No evidence of this variant found in trans with a pathogenic variant for a recessive disorder. CTNNB1-associated disease is autosomal dominant; this criterion is generally not applicable to dominant disorders in the absence of a specific recessive phenotype.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot as assessed by the hotspot analysis. While p.Ala215 is located within the armadillo repeat domain of β-catenin, no domain-specific constraint metrics or hotspot enrichment data were provided to support PM1 application under generic ACMG/AMP rules.
PM2	Met	This variant is present at extremely low frequency in population databases, meeting the PM2 threshold (<0.1%). In gnomAD v2.1, it is observed in 4 of 282,282 alleles (AF=0.00142%, no homozygotes) with a grpmax filtering allele frequency of 2.93e-06. In gnomAD v4.1, it is observed in 62 of 1,613,818 alleles (AF=0.00384%, no homozygotes) with a grpmax FAF of 3.67e-05. It is absent from gnomAD-Canada. All population sub-cohort frequencies are well below 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (p.Ala215) with a different amino acid change was identified in ClinVar or other sources. Automated PM5 candidate harvesting was unable to confirm classic same-residue semantics.	pm5_candidates
PM6	Not met	No de novo observation was identified for this variant. PM6 requires a confirmed de novo event; no such evidence is available.
PP1	Not met	No segregation data in affected family members was identified for this variant.
PP2	Not met	While CTNNB1 missense variants are an established disease mechanism in CTNNB1-associated neurodevelopmental disorder, no gene-level missense constraint metrics (e.g., missense Z-score, observed/expected ratio) were provided to support PP2 application under generic ACMG/AMP rules.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.278 (below typical pathogenic threshold of >0.5), BayesDel score is 0.13681 (benign-leaning), and SpliceAI predicts no significant splice impact (max delta score = 0.02). Combined computational evidence does not support a damaging effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data were available for independent evaluation. The variant has been reported in ClinVar with non-specific indications (one submission for 'Not Provided'), which does not support a highly specific phenotype.	clinvar
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar classifications for this variant are Likely benign (GeneDx) and Uncertain significance (Labcorp/Invitae), neither of which supports a pathogenic assertion.	clinvar
BA1	Not met	The variant is not present at an allele frequency >1% in any gnomAD population. The highest observed subpopulation frequency is 0.026% in EAS_KOR (gnomAD v2.1) and 0.0048% in the Remaining population (gnomAD v4.1), both far below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency does not exceed the 0.3% threshold for BS1 in any population. The highest subpopulation frequency is 0.026% (EAS_KOR in gnomAD v2.1), well below the BS1 cutoff.	gnomad_v2 gnomad_v4
BS2	Not met	No specific evidence of this variant observed in a healthy adult individual in the context of a fully penetrant disorder was identified. While the variant is present in gnomAD (presumed healthy population cohorts), the frequency is too low to independently support BS2, and no individual case-level healthy adult observation data are available.
BS3	Not met	No well-established functional studies demonstrating no damaging effect were identified for this variant. No variant-specific functional data are available from OncoKB or the literature.	oncokb
BS4	Not met	No segregation data in affected families is available to assess lack of segregation with disease.
BP1	Not met	CTNNB1-associated neurodevelopmental disorder is caused by both truncating and missense variants. BP1 is applicable only when a gene primarily causes disease through truncating variants, which is not the case for CTNNB1 where missense variants are an established pathogenic mechanism.
BP2	Not met	No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder was identified. No phase data are available.
BP3	N/A	This criterion applies to in-frame insertions/deletions in repetitive regions; the variant is a missense substitution.
BP4	Not met	Multiple lines of computational evidence do not provide compelling support for a benign effect. REVEL score of 0.278 is in an indeterminate range, BayesDel score of 0.13681 is benign-leaning, and SpliceAI max delta of 0.02 predicts no splicing impact. However, the in silico evidence is not sufficiently strong or concordant to meet BP4; the REVEL score does not clearly fall into a benign range.	revel bayesdel spliceai
BP5	Not met	No evidence of this variant found in a case with an alternate molecular basis for disease was identified.
BP6	Not met	While ClinVar contains a Likely benign classification (GeneDx, SCV001788747), this classification was based on evaluable evidence (criteria provided, single submitter) and does not meet the BP6 requirement of a reputable source report without accessible evidence. The underlying evidence is accessible and has been independently assessed.	clinvar
BP7	N/A	This is a missense variant (c.643G>A, p.Ala215Thr), not a synonymous (silent) variant. BP7 is only applicable to synonymous variants without predicted splice impact.

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