Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001142.2 | MANE Select | 793 nt | 69–644 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (2 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) | 0.03 | 277 bp |
| Donor Loss (DL) | 0.0 | -478 bp |
| Acceptor Gain (AG) | 0.06 | -2 bp |
| Donor Gain (DG) | 0.0 | 351 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 (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows it is a synonymous change (H73=), not predicted to create a null effect. Therefore, this criterion is not applied.
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 does not change the amino acid (synonymous). Therefore, this criterion is not applied.
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". There are no data on parental testing or de novo occurrence. Therefore, this criterion is not applied.
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". No functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". No case-control or affected‐individual prevalence data are available. Therefore, this criterion is not applied.
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". There is no evidence this position lies in a known hotspot or functional domain. 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 variant is present in gnomAD at a high frequency (MAF 19.8%). Therefore, this criterion is not applied.
PM3 (Not Applied)
According to standard ACMG guidelines the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". No data on trans configuration with a pathogenic variant are available. 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". This variant is synonymous and does not alter protein length. 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". This variant is synonymous, not 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". No de novo data are available. 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". No family segregation data are available. 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". This variant 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 (e.g., conservation, splicing impact)". Computational evidence (SpliceAI max score 0.06) does not support a deleterious effect. Therefore, this criterion is not applied.
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". No specific phenotype or family history data are available. 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". No reputable source reports this variant as pathogenic. Therefore, this criterion is not applied.
BA1 (Stand Alone)
According to standard ACMG guidelines the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The variant has MAF 19.8% (gnomAD), well above thresholds. Therefore, this criterion is applied at Stand Alone strength.
BS1 (Strong)
According to standard ACMG guidelines the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The variant's frequency of 19.8% exceeds any expected disease frequency. Therefore, this criterion is applied at Strong strength.
BS2 (Not Applied)
According to standard ACMG guidelines the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". No direct data confirming healthy individuals carrying this variant are available. 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". No functional studies are 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". No family segregation data are available. 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 LoF causes disease". This variant is synonymous. 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". No such cis/trans data are available. 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". This variant is a single‐nucleotide change, not an in‐frame 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". SpliceAI score is 0.06 (below thresholds) and other in silico tools show no deleterious effect. Therefore, this criterion is applied at Supporting strength.
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". No such case data are available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". ClinVar records (2 labs) list this variant as Benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to standard ACMG guidelines the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". This is a synonymous change (H73=) and SpliceAI score is 0.06. Therefore, this criterion is applied at Supporting strength.