NM_001904.3:c.47C>T

CTNNB1 · NP_001895.1:p.(Pro16Leu) · NM_001904.3

GRCh37: chr3:41266050 C>T · GRCh38: chr3:41224559 C>T

Gene: CTNNB1 Transcript: NM_001904.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CTNNB1

Transcript

NM_001904.3

Protein

NP_001895.1:p.(Pro16Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001904.3:c.47C>T (p.Pro16Leu) is a missense variant in CTNNB1 absent from gnomAD v2.1 and v4.1 population databases (PM2).

Multiple in silico tools (REVEL 0.153, BayesDel -0.111, SpliceAI max delta 0.01) concordantly predict a neutral effect (BP4).

No de novo observations, case-control data, functional studies, segregation data, or ClinVar classifications are available for this variant.

The variant has been reported once in the somatic COSMIC database (COSV62719848) but has no established somatic or germline clinical significance.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), this variant is classified as a Variant of Uncertain Significance (VUS).

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	NM_001904.3:c.47C>T is a missense variant (p.Pro16Leu). PVS1 applies only to null variants (nonsense, frameshift, or canonical +/-1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) classifies this variant as bucket 'other' and does not support application of a generic PVS1 downgrade framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	PS1 requires a different nucleotide change at the same codon with established pathogenicity. No alternate pathogenic variant at codon 16 (e.g., c.47C>G, c.47C>A) is present in ClinVar or the literature.
PS2	Not assessed	PS2 requires a de novo observation with confirmed paternity and maternity. No de novo occurrence of NM_001904.3:c.47C>T has been identified in any public database or literature.
PS3	Not assessed	PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No variant-specific functional studies (reporter assays, protein stability, degradation, or MAVE data) were identified for p.Pro16Leu.
PS4	Not assessed	PS4 requires significantly increased prevalence of the variant in affected individuals versus controls. This variant is absent from gnomAD (v2.1, v4.1) and has only a single somatic occurrence in COSMIC (COSV62719848). No case-control data are available for statistical comparison.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 requires both PM5-level evidence (a different pathogenic missense at the same residue) and PS3-level functional data. Neither PM5 nor PS3 evidence is available for this variant.
PM1	Not met	p.Pro16 lies in the N-terminal domain (residues 1-138) but is N-terminal to the well-characterized GSK-3beta phosphorylation hotspot at codons 32-45. Cancer Hotspots confirms this residue is not in a statistically significant mutational hotspot, and no critical functional domain has been defined at this exact position.
PM2	Met	NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1 population databases, meeting the <0.1% threshold for PM2 in the non-VCEP generic ACMG/AMP framework.	gnomad_v2 gnomad_v4
PM5	Not assessed	PM5 requires a different pathogenic missense change at the same residue (Pro16). No pathogenic missense comparator at codon 16 was identified in ClinVar. The PM5 candidate search returned zero candidates at this residue.	pm5_candidates
PM6	Not assessed	PM6 applies to presumed de novo variants without confirmed paternity/maternity. No de novo observation (presumed or confirmed) of NM_001904.3:c.47C>T exists in the literature or databases.
PP1	Not assessed	PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data are available for NM_001904.3:c.47C>T.
PP2	Not assessed	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. CTNNB1 has both missense and truncating pathogenic variants. HCI prior data are unavailable for this gene, precluding assessment of missense constraint. Cannot be applied without constraint metrics.
PP3	Not met	Multiple in silico tools support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero, benign-leaning), and SpliceAI max delta score 0.01 (no predicted splicing impact). No computational tool predicts a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	PP4 requires a patient phenotype or family history highly specific for the gene. No clinical phenotype data are available for individuals carrying NM_001904.3:c.47C>T.
PP5	Not assessed	PP5 requires a reputable source to have reported the variant as pathogenic. This variant is absent from ClinVar; no reputable source has classified it.
BA1	Not met	BA1 requires an allele frequency >1% (non-VCEP threshold). NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% (non-VCEP threshold), greater than expected for the disorder. NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	BS2 requires observation of the variant in a healthy adult individual, in a gene where full penetrance is expected at an early age. NM_001904.3:c.47C>T has not been observed in any control population.
BS3	Not assessed	BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect. No functional studies testing p.Pro16Leu were identified.
BS4	Not assessed	BS4 requires nonsegregation of the variant with disease in affected family members. No segregation data exist for NM_001904.3:c.47C>T.
BP1	Not met	BP1 applies to a missense variant in a gene where primarily truncating variants cause disease. Although most CTNNB1 syndrome-associated variants are truncating (nonsense/frameshift), missense variants are an established disease mechanism in CTNNB1-associated neurodevelopmental disorder. Thus BP1 is not met.
BP2	Not assessed	BP2 requires observation in trans with a known pathogenic variant for a recessive disorder, or in cis with a pathogenic variant for a dominant disorder. No phase data are available for NM_001904.3:c.47C>T.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. The variant is a single nucleotide substitution.
BP4	Met	Multiple lines of computational evidence support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico predictors are concordant for a neutral effect.	revel bayesdel spliceai
BP5	Not assessed	BP5 requires identification of an alternate molecular basis for disease in a case carrying the variant. No such data are available for individuals with NM_001904.3:c.47C>T.
BP6	Not assessed	BP6 requires a reputable source to have reported the variant as benign. This variant is absent from ClinVar; no reputable source has classified it.
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_001904.3:c.47C>T is a missense variant (p.Pro16Leu), not a synonymous change.

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