Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_002691.2 | Alternative | 3470 nt | 57–3380 |
| NM_002691.4 | MANE Select | 3436 nt | 46–3369 |
| NM_002691.1 | Alternative | 3443 nt | 54–3377 |
| NM_002691.3 | Alternative | 3464 nt | 70–3393 |
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) | 0.15 | 18 bp |
| Donor Loss (DL) | 0.01 | 122 bp |
| Acceptor Gain (AG) | 0.14 | -57 bp |
| Donor Gain (DG) | 0.0 | 13 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LoF) is a known mechanism of disease." The evidence for this variant shows: it is an intronic substitution 13 bases upstream of the exon, not affecting canonical ±1 or 2 splice sites, and not predicted to cause a null effect. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the definition of a null variant according to the rule.
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 for this variant shows: no known amino acid change since it is intronic and protein change is unknown. Therefore, this criterion is not applied at Not Applied strength because there is no amino acid change or known pathogenic variant match.
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." The evidence for this variant shows: no information on de novo status. Therefore, this criterion is not applied at Not Applied strength because de novo status is unknown.
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." The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied at Not Applied strength because prevalence data is absent.
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." The evidence for this variant shows: it is in an intronic region outside any known mutational hotspot or functional domain. Therefore, this criterion is not applied at Not Applied strength because it does not reside in a defined hotspot or critical domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows: it is absent from population databases including gnomAD (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is not found in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no data on phase or trans occurrence. Therefore, this criterion is not applied at Not Applied strength because trans data is lacking.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it does not alter protein length as it is non-coding. Therefore, this criterion is not applied at Not Applied strength because it does not change protein length.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before." The evidence for this variant shows: it is intronic and not a missense change. Therefore, this criterion is not applied at Not Applied strength because it is not a missense variant.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied at Not Applied strength because de novo status is not assessed.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at Not Applied strength because segregation data is unavailable.
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 and where missense variants are a common mechanism of disease." The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied at Not Applied strength because it is non-coding.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: mixed in silico predictions with a low CADD score (1.31) and SpliceAI score (0.15) indicating no significant impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support a deleterious effect.
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." The evidence for this variant shows: no phenotype or family history data are provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is unknown.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence." The evidence for this variant shows: not found in ClinVar or other reputable databases. Therefore, this criterion is not applied at Not Applied strength because no reputable pathogenic report exists.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or ExAC." The evidence for this variant shows: MAF=0% in population databases. Therefore, this criterion is not applied at Not Applied strength because allele frequency is below the threshold.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not high.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant, X-linked or mitochondrial disorder with full penetrance expected at an early age." The evidence for this variant shows: no reports in healthy individuals. Therefore, this criterion is not applied at Not Applied strength because no observation in healthy adults.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is unavailable.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss of function causes disease." The evidence for this variant shows: it is non-coding. Therefore, this criterion is not applied at Not Applied strength because it is not a missense variant.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows: no cis/trans data available. Therefore, this criterion is not applied at Not Applied strength because phase information is lacking.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: it is not an indel. Therefore, this criterion is not applied at Not Applied strength because it does not meet the indel requirement.
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." The evidence for this variant shows: low CADD score (1.31) and SpliceAI score (0.15) predicting no significant splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence indicates a lack of impact.
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." The evidence for this variant shows: no case reports with alternate molecular basis. Therefore, this criterion is not applied at Not Applied strength because such data are absent.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence." The evidence for this variant shows: not found in ClinVar or other reputable databases. Therefore, this criterion is not applied at Not Applied strength because no reputable benign report exists.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "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 at Not Applied strength because it does not meet the synonymous variant requirement.