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) | 0.01 | -11 bp |
| Donor Loss (DL) | 0.02 | -117 bp |
| Acceptor Gain (AG) | 0.03 | -34 bp |
| Donor Gain (DG) | 0.0 | -346 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, PVS1 applies to null variants in a gene where loss of function is a known mechanism of disease (Very Strong). The evidence for this variant shows it is an intronic change at position c.63-11, not affecting canonical ±1/2 splice sites. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 applies when the variant leads to the same amino acid change as a known pathogenic variant (Strong). The evidence for this variant shows it is intronic and does not alter an amino acid. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 applies to confirmed de novo variants in a patient with the disease and no family history (Strong). The evidence for this variant shows no information on de novo status or parental testing. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 applies when well-established functional studies support a damaging effect (Strong). The evidence for this variant shows no functional characterization has been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 applies when prevalence in affected individuals is significantly increased compared with controls (Strong). The evidence for this variant shows no case–control data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 applies to variants located in a mutational hot spot or well-established functional domain without benign variation (Moderate). The evidence for this variant shows no hotspot or domain involvement. 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)" (Moderate). The evidence for this variant shows it is absent from population databases including gnomAD. Therefore, this criterion is applied at Moderate strength because the variant is not found in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies when detected in trans with a pathogenic variant in recessive disorders (Moderate). 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, PM4 applies to protein length changes due to in-frame indels or stop-loss variants (Moderate). The evidence for this variant shows no change in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been seen (Moderate). The evidence for this variant shows it is intronic and not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation of paternity/maternity (Moderate). The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 applies to co-segregation with disease in multiple affected family members (Supporting). The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to a missense variant in a gene with low benign missense variation rate and where missense is a common disease mechanism (Supporting). The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 applies when multiple lines of computational evidence support a deleterious effect (Supporting). The evidence for this variant shows in silico tools (SpliceAI, CADD) predict no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 applies to a patient's phenotype highly specific for a disease with a single genetic etiology (Supporting). The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic without accessible evidence (Supporting). The evidence for this variant shows no such report. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 applies when 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, BS1 applies when allele frequency is greater than expected for the disorder (Strong). The evidence for this variant shows it is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 applies when observed in healthy adult individuals for fully penetrant disorders (Strong). The evidence for this variant shows no healthy individual data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 applies when well-established functional studies show no damaging effect (Strong). The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 applies when there is lack of segregation in affected family members (Strong). The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to a missense variant in a gene where only loss of function causes disease (Supporting). The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant (Supporting). The evidence for this variant shows no such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions without known function (Supporting). The evidence for this variant shows no 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 (conservation, evolutionary, splicing impact, etc.)" (Supporting). The evidence for this variant shows SpliceAI score 0.03 and low CADD score, indicating no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational data predict no impact.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when the variant is found in a case with an alternate molecular basis for disease (Supporting). The evidence for this variant shows no such cases. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign without accessible evidence (Supporting). The evidence for this variant shows no such report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to a synonymous variant with no predicted impact on splicing (Supporting). The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.