Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006231.4 | MANE Select | 7823 nt | 28–6888 |
| NM_006231.2 | Alternative | 7859 nt | 45–6905 |
| NM_006231.3 | RefSeq Select | 8024 nt | 210–7070 |
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 | 11 bp |
| Donor Loss (DL) | 0.0 | 224 bp |
| Acceptor Gain (AG) | 0.0 | -211 bp |
| Donor Gain (DG) | 0.0 | -407 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 is a known mechanism of disease'. The evidence for this variant shows: it is a synonymous change (S752=), not predicted to cause loss of function. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: it is a synonymous change with no amino acid alteration. Therefore, this criterion is not applied because there is no amino acid change.
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 data on de novo status or parental testing. Therefore, this criterion is not applied due to lack 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 studies 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: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or cohort data. Therefore, this criterion is not applied due to lack of 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: it is a synonymous change outside of known functional domains. 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 evidence for this variant shows: not present in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
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 information on zygosity or trans configuration. Therefore, this criterion is not applied.
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 is a synonymous variant with no protein length change. Therefore, this criterion is not applied.
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: it is synonymous, not a missense. Therefore, this criterion is not applied.
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 assumption data. Therefore, this criterion 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'. The evidence for this variant shows: no family segregation data. Therefore, this criterion 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 and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
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 results leaning benign, SpliceAI predicts no impact. Therefore, this criterion is not applied because computational evidence does not support deleterious 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 specificity data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without accessible evidence'. The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (stand-alone)'. The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
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%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
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.
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. Therefore, this criterion is not applied.
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 synonymous, not missense. Therefore, this criterion is not applied.
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 phasing data. Therefore, this criterion is not applied.
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 a single nucleotide change, not an 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'. The evidence for this variant shows: SpliceAI scores of 0 predicting no splicing impact, a CADD score of 0.54 indicating low deleteriousness. Therefore, this criterion is applied at Supporting strength because computational tools support no 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 such case reports. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without accessible evidence'. The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Supporting)
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 a silent (S752=) change with SpliceAI scores of 0 for potential splice site alterations. Therefore, this criterion is applied at Supporting strength because it is a synonymous variant with no predicted splicing impact.