NM_001904.4:c.362A>C

CTNNB1 · NP_001895.1:p.(Asn121Thr) · NM_001904.4

GRCh37: chr3:41266565 A>C · GRCh38: chr3:41225074 A>C

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Asn121Thr)

gnomAD AF

6.195356951686129e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 is met at moderate strength: this variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,112 alleles, AF=6.2e-07) and gnomAD Canada (2/18,420 alleles, AF=0.01%), all well below the 0.1% population frequency threshold.

BP4 is met at supporting benign strength: multiple in silico predictors (REVEL 0.176, BayesDel -0.206, SpliceAI max delta 0.19) do not predict a damaging effect on protein function or splicing.

All pathogenic criteria other than PM2 are not met: PS3 (no functional data), PP3 (in silico predictors favor benign, not pathogenic), PM1 (not in a hotspot or critical functional residue), PM5 (no pathogenic comparators at same residue), PS1/PS5 (no alternative nucleotide changes at same codon), PP5 (ClinVar VUS, not 3-star pathogenic).

All benign criteria other than BP4 are not met: BA1/BS1 (population frequency too low), BP1 (missense is a known disease mechanism in CTNNB1), BP6 (ClinVar is VUS, not benign).

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the overall classification is Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules. The moderate evidence for rarity is partially offset by computational evidence suggesting no functional impact.

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
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a single-nucleotide missense substitution.
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans; CTNNB1-associated disease is autosomal dominant.
PM4	N/A	PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss); this is a single-nucleotide missense substitution.
PVS1	N/A	Missense substitution (p.Asn121Thr) does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence that a different nucleotide substitution at codon 121 producing the same amino acid change (p.Asn121Thr) has been reported as pathogenic in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No de novo data available for this variant; both maternity and paternity confirmation would be required.
PS3	Not met	No variant-specific functional data identified. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. No publications with experimental characterization of N121T were identified in the available literature.	oncokb
PS4	Not met	No case-control or prevalence data comparing affected individuals to controls available for this variant.
PS5	Not met	No alternative nucleotide change at codon 121 producing the same p.Asn121Thr amino acid substitution has been reported as pathogenic.	clinvar
PM1	Not met	Residue 121 is not in a statistically significant mutational hotspot (cancerhotspots.org negative). While the N-terminal domain (aa 1-150) of β-catenin contains the GSK3β-mediated degradation signal, residue N121 is not one of the critical phosphorylation sites (S33, S37, T41, S45) and no literature specifically identifies N121 as a functionally critical residue within this domain.	oncokb
PM2	Met	This variant is present at extremely low frequency in population databases, well below the 0.1% threshold: absent from gnomAD v2.1 and present in only 1/1,614,112 alleles in gnomAD v4.1 (AF=6.2e-07, 0.000062%). gnomAD Canada reports 2/18,420 alleles (AF=0.01%, highest subpopulation NFE AF=0.017%).	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM5	Not met	No pathogenic missense variants at the same amino acid residue (codon 121) were identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants.	pm5_candidates clinvar
PM6	Not met	No de novo observation reported for this variant. Confirmation of maternity and paternity would be required to apply this criterion.
PP1	Not met	No co-segregation data available for this variant.
PP2	Not met	Although CTNNB1 missense variants are a known mechanism of neurodevelopmental disease (CTNNB1 syndrome), no specific missense constraint metric (e.g., Z-score) was available to establish a low rate of benign missense variation in this gene.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold, favors benign), BayesDel score -0.206 (negative, favors benign), SpliceAI max delta 0.19 (below 0.2 threshold, no splicing impact predicted).	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or clinical data available for assessment.
PP5	Not met	ClinVar classification is Uncertain significance from a single clinical laboratory (Labcorp/Invitae), with review status 'criteria provided, single submitter' (1 star). PP5 requires a 3-star expert panel classification as pathogenic to apply at supporting strength. The single-submitter VUS classification does not meet this threshold.	clinvar
BA1	Not met	The highest observed allele frequency is 0.017% (gnomAD Canada, NFE population), which is well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The highest observed allele frequency is 0.017% (gnomAD Canada, NFE population), which is below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data available regarding observation of this variant in healthy adult individuals to assess for full-penetrance expectation mismatch.
BS3	Not met	No functional studies demonstrating a neutral or benign effect for this variant have been identified.	oncokb
BS4	Not met	No segregation data available to assess lack of co-segregation with disease.
BP1	Not met	CTNNB1 missense variants are a known disease mechanism for CTNNB1-associated neurodevelopmental disorder (PMID:33350591). The gene does not exhibit a disease mechanism restricted exclusively to truncating variants.
BP2	Not met	No data available on observation of this variant in trans with a pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest this variant does not impact protein function: REVEL score 0.176 (below disease-causing threshold of 0.5), BayesDel score -0.206 (negative, favors benign), and SpliceAI max delta 0.19 (no predicted splicing impact).	revel bayesdel spliceai
BP5	Not met	No data available indicating this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar classification is Uncertain significance (1 star, single submitter), not benign. BP6 requires a 3-star expert panel classification as benign to apply at supporting strength.	clinvar
BP7	N/A	This is a missense variant (p.Asn121Thr), not a synonymous variant with no predicted splice impact.

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