Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
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) | 0.01 | 13 bp |
| Donor Loss (DL) | 0.0 | 36 bp |
| Acceptor Gain (AG) | 0.71 | 0 bp |
| Donor Gain (DG) | 0.0 | -227 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD.' The evidence for this variant shows it is a duplication at c.793-11_794, outside the canonical ±1/2 splice positions. Therefore, PVS1 is not applied because the variant does not meet the VCEP PVS1 splice‐site criteria.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence shows no known pathogenic variant encoding the same amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' There are no data on de novo occurrence for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well‐established functional studies supportive of a damaging effect on the gene or gene product.' No functional studies have been performed for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with controls.' There is no case‐control or case series data. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation.' This variant does not lie in a recognized hotspot or critical domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence shows the variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength because it meets the VCEP frequency criterion.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' No such trans observations are available for this dominant‐acting gene. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in‐frame insertions/deletions in a non‐repeat region or stop‐loss variants.' The impact of this intronic/exonic duplication on protein length is unknown. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Missense change at an amino acid residue where a different missense change is pathogenic.' This variant is not a missense change. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo without confirmation of paternity and maternity.' No presumed de novo data exist. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co‐segregation with disease in multiple affected family members.' No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation.' This variant is not a missense change. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Predicted splice defect for non‐canonical splicing nucleotides using SpliceAI with delta score ≥0.2.' The evidence shows SpliceAI predicts an acceptor gain with a score of 0.71. Therefore, PP3 is applied at Supporting strength because the in silico splice prediction meets the threshold.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' No tumor or clinical phenotype data are available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' The variant is not reported in ClinVar or other databases. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'GnomAD v4 filtering allele frequency ≥0.001 (0.1%).' The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'GnomAD v4 filtering allele frequency ≥0.0001 and <0.001.' The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Co‐occurrence in trans with a known pathogenic variant in the same gene in a patient without CMMRD.' No co‐occurrence data exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Calibrated functional assays showing no deleterious effect or synonymous/intronic variants with no mRNA aberration.' No functional or RNA assay data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' No segregation data exist. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' This variant is not missense. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder.' No such data exist. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame insertions/deletions in a repetitive region without a known function.' The variant’s repetitive context is unknown. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting SpliceAI predicts no splicing impact with delta score ≤0.1.' SpliceAI score is 0.71, indicating impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' No alternate molecular findings are reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign.' No such reports exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting A synonymous or intronic variant at or beyond -21/+7.' This variant lies at -11, within the region not covered by BP7. Therefore, BP7 is not applied.