Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_021946.4 | Alternative | 7127 nt | 45–5180 |
| NM_021946.2 | Alternative | 6740 nt | 115–5250 |
| NM_021946.5 | Alternative | 7243 nt | 173–5308 |
| NM_021946.3 | Alternative | 7252 nt | 170–5305 |
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) | 0.0 | 205 bp |
| Donor Loss (DL) | 0.02 | 14 bp |
| Acceptor Gain (AG) | 0.0 | -242 bp |
| Donor Gain (DG) | 0.0 | 2 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1 – 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 exon deletion in a LoF gene)'. The evidence for this variant shows: it is an intronic variant at position +16 outside the canonical splice sites and does not create a null effect. Therefore, this criterion is not applied because the variant is not a null variant at canonical splice sites.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no amino acid change is predicted. Therefore, this criterion is not applied because the variant does not produce an amino acid change matching a known pathogenic variant.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied due to lack of confirmed de novo evidence.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to absence of functional data.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no data on occurrence in affected cohorts. Therefore, this criterion is not applied due to lack of case–control data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: it lies in an intronic region outside known functional domains. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: MAF = 0.0114% in gnomAD, extremely rare. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no data on detection in trans with a pathogenic allele. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a single-nucleotide intronic change, not affecting protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: no missense effect. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no data on assumed de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is intronic, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: in silico predictors (CADD = 0.14, SpliceAI max = 0.02) suggest no deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotypic or family history data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'BA1 – Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: MAF = 0.0114%, well below the >5% threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF is very low and not greater than expected. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'BS2 – Observed in healthy adult individuals for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age'. The evidence for this variant shows: no data on observation in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'BS3 – Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'BS4 – Lack of segregation in affected family members'. The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 – Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: it is intronic and not a missense change. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: single-nucleotide change outside repetitive regions. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact on gene/gene product'. The evidence for this variant shows: SpliceAI max score 0.02 and CADD score 0.14 indicate no deleterious effect on splicing or protein. Therefore, this criterion is applied at Supporting strength because computational evidence supports benign impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is intronic, not synonymous. Therefore, this criterion is not applied.