Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000535.6 | Alternative | 5156 nt | 88–2676 |
| NM_000535.4 | Alternative | 2836 nt | 88–2676 |
| NM_000535.7 | MANE Select | 5093 nt | 31–2619 |
| NM_000535.5 | Alternative | 2851 nt | 88–2676 |
| NM_000535.3 | Alternative | 2820 nt | 57–2645 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (1 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) | 0.02 | 256 bp |
| Donor Loss (DL) | 0.0 | -60 bp |
| Acceptor Gain (AG) | 0.02 | -281 bp |
| Donor Gain (DG) | 0.05 | 8 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 798 in PMS2…". The evidence for this variant shows it is a synonymous substitution (no PTC). Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "Strong: A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established as Pathogenic…". The evidence for this variant shows no amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG for PS2: requires confirmed de novo occurrence. No de novo data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG for PS3: "Functional studies supportive of a damaging effect on the gene or gene product." No functional assay data are available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG for PS4: requires case–control or family-based statistical evidence of pathogenicity. No such data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG for PM1: requires variant in a mutational hot spot or well-established functional domain without benign variation. This variant is synonymous outside known hotspots. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2: "Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows absence from population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines for PM3: requires observed in trans with a pathogenic variant in a recessive disorder. No such data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG for PM4: pertains to protein length changes. This is a synonymous variant. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: requires missense change at a residue with a different pathogenic missense. This is synonymous. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG for PM6: unconfirmed de novo. No de novo evidence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG for PP1: requires co-segregation with disease. No segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG for PP2: pertains to missense variants in genes with low benign variation. This is synonymous. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3: supporting for non-canonical splice or high prior missense. SpliceAI score is 0.05 (no impact) and variant is synonymous. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG for PP4: requires specific phenotype or family history. No phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG for PP5: requires reputable source reporting pathogenic. No such report. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Stand Alone: GnomAD v4 grpmax filtering allele frequency ≥0.0028." Variant MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Strong: GnomAD v4 grpmax filtering allele frequency ≥0.0001 and <0.001." Variant MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2: requires co-occurrence in trans with a known pathogenic variant. No such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Strong: Synonymous substitutions with no associated mRNA aberration as determined by laboratory assays." No laboratory mRNA assay data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG for BS4: requires lack of segregation with disease. No segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG for BP1: pertains to missense in genes where only truncating variants cause disease. This is synonymous. Therefore, not applied.
BP2 (Not Applied)
According to standard ACMG for BP2: observed in trans with a pathogenic variant in a dominant disorder. No such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG for BP3: in-frame indels in repetitive regions. Not applicable to synonymous SNV. Therefore, not applied.
BP4 (Supporting)
According to VCEP guidelines for BP4: "Supporting: For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1." SpliceAI max delta=0.05. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG for BP5: requires variant found in a case with an alternate molecular cause. No such case data. Therefore, not applied.
BP6 (Supporting)
According to standard ACMG for BP6: "Supporting: Reputable source recently reports variant as benign but evidence not available to laboratory." ClinVar reports Likely benign/Benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to standard ACMG for BP7: "Supporting: A synonymous variant at or beyond -21/+7 exonic with no predicted splice impact." SpliceAI delta ≤0.1. Therefore, this criterion is applied at Supporting strength.