Variant classification summary

NM_001904.4:c.802G>T

CTNNB1 · NP_001895.1:p.(Gly268Ter) · NM_001904.4

GRCh37: chr3:41267218 G>T · GRCh38: chr3:41225727 G>T

Gene: CTNNB1 Transcript: NM_001904.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Gly268Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001904.4:c.802G>T (NP_001895.1:p.Gly268Ter) is a nonsense variant in exon 6 of 15 exons in CTNNB1, predicted to result in premature protein termination and nonsense-mediated decay of the transcript.

2

CTNNB1 loss-of-function is an established disease mechanism for autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; MIM 615075), supported by ClinGen haploinsufficiency score of 3 and multiple publications describing pathogenic germline nonsense and frameshift variants.

3

This variant is absent from gnomAD v2.1 and v4.1 (0 alleles across >140,000 individuals) and absent from gnomAD-Canada v1.0, consistent with a rare pathogenic variant under strong purifying selection.

4

The variant is not present in ClinVar, and no functional studies, cosegregation data, or detailed clinical phenotypes for individuals carrying this variant were available in the evidence record.

5

Applying the generic ACMG/AMP 2015 classification framework (Richards et al. 2015, PMID:25741868), the combination of one very strong criterion (PVS1) and one moderate criterion (PM2) meets the threshold for Likely Pathogenic (1 Very Strong + 1 Moderate).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	NM_001904.4:c.802G>T is a nonsense variant in exon 6 of 15 exons, predicted to result in a premature termination codon (NP_001895.1:p.Gly268Ter) and trigger nonsense-mediated decay (stop codon >50 nt upstream of the last exon-exon junction). CTNNB1 loss-of-function is an established disease mechanism for autosomal dominant neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; MIM 615075), supported by ClinGen haploinsufficiency score of 3 and multiple clinical publications describing germline nonsense and frameshift variants as pathogenic. Per the ClinGen SVI PVS1 decision tree (PMC6185798), a nonsense variant in a gene with an established LoF mechanism where NMD is predicted qualifies for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is designed for missense variants where a different nucleotide change results in the same amino acid substitution as an established pathogenic variant. For this nonsense variant (c.802G>T, p.G268*), no different nucleotide change at codon 268 creating a premature stop codon has been identified as a known pathogenic comparator in ClinVar or the available evidence.
PS2	Not assessed	The exploratory evidence pipeline identified a potential confirmed de novo report for this variant (PMID:32222192, Li et al. 2020 — reported de novo heterozygous c.802G>T in a patient with intellectual disability, microcephaly, and speech delay, with both parents confirmed negative). However, full-text is not available for verification per mandatory citation policy. Without confirmed parentage documentation in the retrievable evidence record, PS2 cannot be applied.
PS3	Not assessed	No well-established functional studies (in vitro or in vivo) of NM_001904.4:c.802G>T are available in the evidence record. OncoKB lists an Unknown Oncogenic Effect with no variant-specific functional data. COSMIC reports no somatic entries for this variant.	oncokb
PS4	Not assessed	The variant is absent from ClinVar, so affected individuals cannot be tallied from that source. No verified publications containing proband counts for this exact variant were accessible for review. While the variant is completely absent from gnomAD (supporting rarity), the number of independently ascertained affected probands required for PS4 cannot be confirmed from the available evidence.
PS5	Not assessed	No ClinVar entry exists for this variant, and no verified publications report a different pathogenic variant at the same amino acid position (codon 268) that could serve as a PS5 comparator. Without a validated comparator, PS5 cannot be applied.
PM1	Not met	The variant does not lie in a known mutational hotspot or critical functional domain. Cancerhotspots.org shows residue G268 is not a statistically significant hotspot. COSMIC has no entries for this variant. No germline mutational hotspot has been established for CTNNB1 exon 6 by a ClinGen VCEP.
PM2	Met	NM_001904.4:c.802G>T is completely absent from large population databases. It is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles across >140,000 individuals), and gnomAD-Canada v1.0 (0 alleles). Under generic ACMG/AMP non-VCEP cutoffs, absence from population databases supports PM2 at moderate strength.	gnomad_v2 gnomad_v4
PM5	N/A	The PM5 candidate search returned no same-residue comparator variants. PM5 is designed for missense variants at the same amino acid residue as a known pathogenic missense change. No applicable comparator exists for this nonsense variant at codon 268.
PM6	Not assessed	The exploratory evidence pipeline identified a possible assumed de novo record for this variant in DECIPHER, but parentage confirmation status could not be verified. No publications with de novo status (without confirmed parentage) for this exact variant are accessible for full-text review. Without verified evidence of de novo occurrence without parental confirmation, PM6 cannot be applied.
PP1	Not assessed	No cosegregation data is available. CTNNB1-related neurodevelopmental disorders are typically de novo with rare familial transmission. No published families with multiple affected members carrying this variant were identified in the available evidence.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. NM_001904.4:c.802G>T is a nonsense variant, not a missense variant. HCI Prior data is not available for this gene.
PP3	Not met	Multiple lines of computational evidence supporting a deleterious effect are not available. REVEL score is unavailable for this variant. BayesDel score of 0.66 provides a single in silico predictor in the damaging direction, but SpliceAI predicts no significant splice impact (max delta score = 0.02). A single moderately elevated BayesDel score does not constitute multiple lines of computational evidence. Furthermore, the predicted null effect of this nonsense variant is already captured by PVS1; applying PP3 for the same molecular consequence would constitute double-counting under ACMG/AMP guidance.	spliceai bayesdel
PP4	Not assessed	No detailed clinical phenotype information for individuals carrying NM_001904.4:c.802G>T was available for review. Patient phenotype specificity and fit to the CTNNB1-related neurodevelopmental disorder spectrum cannot be evaluated from the current evidence record.
PP5	Not assessed	No ClinVar entry exists for NM_001904.4:c.802G>T. PP5 requires a pathogenic classification from a reputable source (e.g., ClinVar); without such an entry, this criterion cannot be applied.
BA1	Not met	BA1 requires an allele frequency >5% in any general population. NM_001904.4:c.802G>T is completely absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles). This threshold is not met.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic non-VCEP cutoffs). The variant is absent from gnomAD v2.1 and v4.1 (0 alleles). This threshold is not met.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult individual for a fully penetrant dominant disorder. NM_001904.4:c.802G>T is completely absent from gnomAD across all populations. No confirmed observation in a healthy adult exists to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing are available for NM_001904.4:c.802G>T.
BS4	N/A	BS4 evaluates lack of segregation in affected family members. CTNNB1-related neurodevelopmental disorders are typically de novo; no multigenerational family structures with affected members exist to evaluate segregation for this variant. BS4 is not applicable in this clinical context.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. NM_001904.4:c.802G>T (p.Gly268Ter) is itself a truncating (nonsense) variant, not a missense change. BP1 is not applicable.
BP2	N/A	BP2 applies when a variant is observed in trans with a known pathogenic variant for a recessive disorder. CTNNB1-related neurodevelopmental disorder is autosomal dominant (MIM 615075); no biallelic occurrences of CTNNB1 variants have been reported. BP2 is not applicable in this clinical context.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. BayesDel score of 0.66 is in the damaging direction, not the benign direction. SpliceAI predicts no splice impact (max delta 0.02), but this is a nonsense variant that introduces a premature stop codon — the predicted molecular consequence is damaging, not benign. Computational evidence does not support BP4.	bayesdel spliceai
BP5	Not assessed	No ClinVar entry exists for NM_001904.4:c.802G>T, and no verified publication reports a benign classification for this variant from a reputable source. BP5 cannot be assessed without such evidence.
BP6	Not assessed	No ClinVar entry exists for NM_001904.4:c.802G>T with a benign classification from a reputable source. BP6 cannot be assessed without such evidence.
BP7	N/A	BP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001904.4:c.802G>T is a nonsense variant that creates a premature termination codon (p.Gly268Ter). BP7 is not applicable.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; NM_001904.4:c.802G>T is a single-nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CTNNB1-related neurodevelopmental disorder is autosomal dominant (MIM 615075).
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_001904.4:c.802G>T is a nonsense (stop-gain) single-nucleotide substitution.

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