Variant classification summary

NM_001904.4:c.2175C>T

CTNNB1 · NP_001895.1:p.(Gly725=) · NM_001904.4

GRCh37: chr3:41280662 C>T · GRCh38: chr3:41239171 C>T

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Gly725=)

gnomAD AF

6.443506556267922e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting is met because gnomAD v4.1 AF 6.44351e-05 is below 0.0001 with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone satisfies neither a pathogenic nor a benign combination rule, so the final call is VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: parental maternity and paternity confirmation, family history, and proband disease documentation are unavailable.
PS3	Not assessed	Not assessed: no variant-specific functional assay or validated damaging-effect measurement was available for CTNNB1 c.2175C>T (p.Gly725=).	PMID:25741868
PS4	Not met	Not met: no affected-versus-control counts, matched-ancestry frequency comparison, odds ratio, or confidence interval was available for the exact variant.	PMID:25741868 clinvar gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 AF 6.44351e-05 is below the generic PM2 supporting threshold of <=0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: CTNNB1-related neurodevelopmental disorder is autosomal dominant, whereas PM3 is limited to recessive disorders with a confirmed pathogenic variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no documented de novo observation exists, and parental testing or maternity/paternity information is unavailable.
PP1	Not assessed	Not assessed: affected-relative genotypes, phenotype concordance, and the number of informative meioses are not documented.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
PP3	Not met	Not met: the synonymous variant's required SpliceAI max delta is unavailable, so it cannot reach the PP3 supporting threshold of >=0.2.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or family-history details were available to judge specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and the two exact-variant laboratory submissions classify it as Likely benign, not pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 all-comers AF 6.44351e-05 is far below the BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the maximum observed AF is 6.44351e-05, well below the generic BS1 default of 0.01 for this early-onset dominant disorder.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no individual-level healthy adult observation meeting the BS2 age, inheritance, and penetrance requirements.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no variant-specific functional assay or validated evidence showing no damaging effect on protein function or splicing was available.	PMID:25741868
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are reported for evaluating non-segregation.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a synonymous variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no pathogenic partner allele or parental, offspring, segregation, or molecular phase data establish cis or trans configuration.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a synonymous variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not 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.	spliceai
BP5	Not assessed	Not assessed: no patient record documents the exact variant together with an alternate molecular basis for the disease.
BP6	Not met	Not met: ClinVar reports Likely benign from two clinical laboratories but zero expert-panel submissions, so no qualifying reputable-source benign report is available.	clinvar
BP7	Not assessed	Not assessed: BP7 requires no splice impact and low conservation, but SpliceAI and qualifying conservation evidence are unavailable.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.