Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_005089.1 | Alternative | 1488 nt | 25–1473 |
| NM_005089.2 | Alternative | 1609 nt | 25–1473 |
| NM_005089.3 | RefSeq Select | 1512 nt | 46–1494 |
| NM_005089.4 | MANE Select | 1479 nt | 13–1461 |
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 | -290 bp |
| Donor Loss (DL) | 0.0 | 66 bp |
| Acceptor Gain (AG) | 0.0 | -343 bp |
| Donor Gain (DG) | 0.0 | -192 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 exon or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: c.1344_1346delCAG is an in-frame deletion of a single amino acid and is not predicted to create a null allele. Therefore, this criterion is not applied at Not Applied strength because the variant does not result in a predicted loss-of-function allele.
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 previously established pathogenic variant results in p.Arg449del. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of an identical amino acid change recorded as pathogenic.
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 occurrence or parental testing. Therefore, this criterion is not applied at Not Applied strength due to absence of de novo evidence.
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 characterization has been reported. Therefore, this criterion is not applied at Not Applied strength because functional data are 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 demonstrating enrichment. Therefore, this criterion is not applied at Not Applied strength due to absence of case prevalence data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: no data on a mutational hot spot or critical domain at residue R449. Therefore, this criterion is not applied at Not Applied strength because domain relevance is unknown.
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: not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from large population datasets.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: no data on trans configuration with another pathogenic variant. Therefore, this criterion is not applied at Not Applied strength due to lack of segregation or phase data.
PM4 (Moderate)
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: c.1344_1346delCAG results in an in-frame deletion of one amino acid (p.Arg449del). Therefore, this criterion is applied at Moderate strength because the variant alters protein length by an in-frame deletion.
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.' The evidence for this variant shows: no other pathogenic variant affecting residue Arg449. Therefore, this criterion is not applied at Not Applied strength because no pathogenic variants at this codon are reported.
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 parental testing data. Therefore, this criterion is not applied at Not Applied strength due to absence of de novo assumption evidence.
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 segregation studies reported. Therefore, this criterion is not applied at Not Applied strength due to lack of family segregation data.
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 an in-frame deletion, not a missense change. Therefore, this criterion is not applied at Not Applied strength.
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/gene product.' The evidence for this variant shows: SpliceAI score 0.01 (no significant splicing impact) and insufficient in silico evidence of deleteriousness. Therefore, this criterion is not applied at Not Applied strength because computational data do not support a damaging effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or family history information provided. Therefore, this criterion is not applied at Not Applied strength due to missing clinical specificity data.
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 authoritative databases. Therefore, this criterion is not applied at Not Applied strength.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder.' The evidence for this variant shows: absent from population databases, not above any threshold. Therefore, this criterion is not applied at Not Applied strength.
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: MAF=0%, below any expected threshold. Therefore, this criterion is not applied at Not Applied strength.
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 due to absence of healthy carrier data.
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.
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 analysis. Therefore, this criterion is not applied at Not Applied strength.
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 an in-frame deletion. Therefore, this criterion is not applied at Not Applied strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant.' The evidence for this variant shows: no phase or companion variant data. Therefore, this criterion is not applied at Not Applied strength.
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: location in non-repetitive region is unknown. Therefore, this criterion is not applied at Not Applied strength due to lack of region characterization.
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: SpliceAI score 0.01 (no splicing impact) and insufficient in silico evidence for deleteriousness. Therefore, this criterion is applied at Supporting strength because computational data support a benign interpretation.
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 diagnoses. Therefore, this criterion is not applied at Not Applied strength.
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: no external benign assertions. Therefore, this criterion is not applied at Not Applied strength.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing and no conservation of the nucleotide.' The evidence for this variant shows: it is a coding in-frame deletion, not synonymous. Therefore, this criterion is not applied at Not Applied strength.