NM_001904.4:c.-48-3dupT

CTNNB1 · NP_001895.1:p.? · NM_001904.4

GRCh37: chr3:41265502 C>CT · GRCh38: chr3:41224011 C>CT

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.?

gnomAD AF

5.672378541770135e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001904.4:c.-48-3dupT is a single-nucleotide T duplication in the 5' UTR of CTNNB1, 48 bases upstream of the initiation codon. It is present in gnomAD v4.1 at an extremely low allele frequency of 0.00057% (9/1,586,636 alleles, no homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada v1.0.

The variant is absent from ClinVar and has not been reported in the published literature. No functional studies, segregation data, de novo observations, or case-control comparisons are available. SpliceAI predicts no significant splicing impact (max delta = 0.01).

The variant has been observed once in somatic cancers (COSMIC COSV115288055), but this does not inform germline pathogenicity.

Only PM2 (supporting) is met. With only one supporting pathogenic criterion and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic rules.

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	Variant NM_001904.4:c.-48-3dup is a single-nucleotide duplication in the 5' UTR (c.-48-3dup), 48 bases upstream of the ATG start codon. It does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) per the ClinGen SVI PVS1 framework (PMC6185798). PVS1 is not applicable to non-coding variants of this type.	pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change at the same position with established pathogenicity. This is a duplication, not a substitution, and no pathogenic variant at this 5' UTR position has been identified. The variant is absent from ClinVar.	clinvar
PS2	Not assessed	No de novo occurrence data available. No publications report this variant in a trio or family context.
PS3	Not assessed	No well-established functional studies available for this variant. SpliceAI delta score of 0.01 does not constitute positive functional evidence of pathogenicity. No literature reports functional characterization of this specific 5' UTR duplication.
PS4	Not assessed	No case-control data available. Variant is absent from ClinVar and no published disease cohorts report this variant.
PS5	N/A	PS5 requires a different pathogenic variant at the same position with an established functional or clinical effect. No pathogenic variant at this 5' UTR position has been established.	clinvar
PM1	Not met	The variant is located in the 5' UTR (c.-48-3dup), not within a known mutational hotspot or critical functional domain of CTNNB1. Hotspot analysis did not identify this residue as significant.
PM2	Met	This variant is present in gnomAD v4.1 at an extremely low allele frequency of 5.67×10⁻⁶ (9/1,586,636 alleles, 0.00057%), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants in coding regions. This is a single-nucleotide duplication in the 5' UTR (c.-48-3dup), outside the coding sequence, and does not alter protein length.
PM5	N/A	PM5 requires a novel missense variant at the same amino acid residue as a known pathogenic missense variant. This variant is a 5' UTR duplication and does not encode an amino acid change. PM5 candidate harvesting was not applicable (eligible_for_classic_pm5_search=false).
PM6	Not assessed	No de novo occurrence data available. No publications report this variant as a confirmed or assumed de novo event.
PP1	Not assessed	No co-segregation data available. No family studies report this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a 5' UTR duplication, not a missense change.
PP3	Not met	Multiple lines of computational evidence supporting a deleterious effect are required. SpliceAI predicts no significant splice impact (max delta = 0.01). REVEL and BayesDel scores are unavailable (not an SNV). HCI prior probability is not supported for CTNNB1. No computational evidence supports a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype or family history data specific to this variant are available. No case reports describe the clinical presentation of individuals carrying this variant.
PP5	Not met	This variant is absent from ClinVar. No reputable source (expert panel, clinical laboratory, or published report) has classified this variant as pathogenic.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 5.67×10⁻⁶ (0.00057%), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 5.67×10⁻⁶ (0.00057%), far below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	Nine alleles are observed in gnomAD v4.1, which excludes individuals with severe pediatric disease. However, without explicit confirmation that these carriers are healthy adults with full phenotypic ascertainment, BS2 cannot be reliably applied. CTNNB1 syndrome is a severe early-onset neurodevelopmental disorder where incomplete penetrance is not expected.	gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not assessed	No non-segregation data available. No family studies report this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is a 5' UTR duplication, not a missense change.
BP2	Not assessed	No data on observation in trans with a pathogenic variant. No phase information available.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This is a single-nucleotide duplication in the 5' UTR, not an in-frame coding indel.
BP4	Not met	Multiple lines of computational evidence suggesting no impact are required. SpliceAI predicts no splice effect (delta = 0.01, one line of evidence). REVEL and BayesDel are unavailable (variant is not an SNV). A single computational data point is insufficient to meet BP4.	spliceai
BP5	Not assessed	No data on an alternate molecular basis for disease in a case carrying this variant.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a 5' UTR duplication, not a synonymous substitution.
PM3	N/A	Skipped per adjudication instructions: trivially not applicable (CTNNB1-associated disorders follow autosomal dominant inheritance; PM3 applies to recessive disorders).

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