Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_024426.4 | Alternative | 3037 nt | 191–1744 |
| NM_024426.6 | MANE Select | 3031 nt | 180–1748 |
| NM_024426.5 | RefSeq Select | 3041 nt | 180–1748 |
| NM_024426.3 | Alternative | 3029 nt | 197–1750 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (20 clinical laboratories) and as benign (1 clinical laboratories)."
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 | 8 bp |
| Donor Loss (DL) | 0.01 | -142 bp |
| Acceptor Gain (AG) | 0.0 | -83 bp |
| Donor Gain (DG) | 0.0 | 8 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 (R369=) change with no predicted impact on splicing. Therefore, this criterion is not applied because the variant does not create a null allele.
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: no amino acid change relative to reference. Therefore, this criterion is not applied because the variant does not alter the protein sequence.
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 parental testing or de novo data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
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 have been performed. Therefore, this criterion is not applied because functional data are not available.
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 in affected individuals. Therefore, this criterion is not applied due to absence 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 any known functional domain or hotspot. Therefore, this criterion is not applied.
PM2 (Not Applied)
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: a global gnomAD allele frequency of 23.6%. Therefore, this criterion is not applied because the variant is common in population databases.
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 phase or trans data are available. Therefore, this criterion is not applied due to lack of trans configuration data.
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: no change in protein length (synonymous). 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: no amino acid change. 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 or family 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 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/gene product." The evidence for this variant shows: computational tools predict no impact (CADD 0.62, SpliceAI ≤0.01). Therefore, this criterion is not applied because computational evidence supports benign impact (BP4).
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 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, but without accessible evidence." The evidence for this variant shows: no reputable source reports pathogenicity. Therefore, this criterion is not applied.
BA1 (Stand Alone)
According to standard ACMG guidelines, the BA1 rule is: "Allele frequency is too high for the disorder." The evidence for this variant shows: a global gnomAD MAF of 23.6%, well above the BA1 threshold. Therefore, this criterion is applied at Stand Alone strength because the allele frequency exceeds the maximum credible frequency.
BS1 (Strong)
According to standard ACMG guidelines, the BS1 rule is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: gnomAD MAF of 23.6%. Therefore, this criterion is applied at Strong strength because the allele frequency is greater than the maximum expected for pathogenic variants.
BS2 (Strong)
According to standard ACMG guidelines, the BS2 rule is: "Observed in healthy individuals with full penetrance expected at an early age." The evidence for this variant shows: 11,532 homozygotes in gnomAD. Therefore, this criterion is applied at Strong strength because the variant is observed in numerous healthy individuals.
BS3 (Not Applied)
According to standard ACMG guidelines, the BS3 rule is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the BS4 rule 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 BP1 rule is: "Missense variant in a gene where only LoF causes disease." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the BP2 rule 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 cis/trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the BP3 rule 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.
BP4 (Supporting)
According to standard ACMG guidelines, the BP4 rule is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: CADD score 0.62 and SpliceAI ≤0.01. Therefore, this criterion is applied at Supporting strength because computational predictions indicate no deleterious effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the BP5 rule is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no case reports with alternate etiology. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports variant as benign, but without accessible evidence." The evidence for this variant shows: ClinVar reports as benign from 20 clinical laboratories. Therefore, this criterion is applied at Supporting strength because reputable sources classify it as benign.
BP7 (Supporting)
According to standard ACMG guidelines, the BP7 rule is: "Synonymous variant with no predicted impact on splicing." The evidence for this variant shows: R369= and SpliceAI ≤0.01. Therefore, this criterion is applied at Supporting strength because it is a silent change with no splicing impact.