Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001904.3 | Alternative | 3720 nt | 269–2614 |
| NM_001904.4 | MANE Select | 3661 nt | 215–2560 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.09 | 397 bp |
| Donor Loss (DL) | 0.09 | -3 bp |
| Acceptor Gain (AG) | 0.0 | -3 bp |
| Donor Gain (DG) | 0.01 | -49 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion)'. The variant is at the +3 splice position, not at a canonical +1 or +2 splice site and does not create a null allele. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. There is no known amino acid change or matching pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. No de novo data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. No functional studies have been reported for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. No case-control or prevalence data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. This variant is at the +3 splice position, not within a known hotspot or functional domain. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The variant is absent from gnomAD, ExAC, 1000 Genomes, and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is not found in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. CTNNB1-associated disease is dominant and no trans data exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. This variant is a splice region change, not an in-frame insertion/deletion. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The variant does not alter an amino acid residue. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. No de novo data exist. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 is: 'Co-segregation with disease in multiple affected family members'. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. This is a splice region variant, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. In silico tools including CADD (2.56) and SpliceAI (0.09) do not predict a damaging effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology'. No phenotype or family history details are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The variant is not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 is: 'Allele frequency is too high for the disorder'. This variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, BS1 is: 'Allele frequency is greater than expected for disorder'. This variant is not observed in population databases. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. No such observations exist. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. No functional studies are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 is: 'Lack of segregation in affected family members'. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 is: 'Missense variant in a gene where only loss of function causes disease'. This is not a missense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. No such observations exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. This variant is not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)'. In silico tools including CADD (score 2.56) and SpliceAI (score 0.09) predict no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports a benign effect.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. No such cases are reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The variant is not reported as benign in any source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 is: 'Synonymous variant with no predicted impact on splicing'. This variant is intronic at +3, not synonymous. Therefore, this criterion is not applied.