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_000535.3 | Alternative | 2820 nt | 57–2645 |
| NM_000535.5 | Alternative | 2851 nt | 88–2676 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (3 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) | 0.0 | -274 bp |
| Donor Loss (DL) | 0.01 | -323 bp |
| Acceptor Gain (AG) | 0.0 | -8 bp |
| Donor Gain (DG) | 0.0 | 100 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PMS2, PVS1 Very Strong applies only to canonical ±1/2 splice site or loss-of-function variants. The variant is at intronic position −8 and is non-coding. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 Strong requires an identical amino acid change to a known pathogenic variant. This variant is intronic and does not alter amino acid sequence. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 Strong/Moderate/Supporting requires confirmed de novo occurrence. No parental or de novo data are available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 requires well-validated functional assays showing a damaging effect. No functional studies have been performed for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 requires statistically significant case-control or segregation data. No case-control data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 Moderate applies to variants in a mutational hot spot or critical domain. This intronic variant lies outside known functional domains. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines for PMS2, PM2 Supporting: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to variants observed in trans with a pathogenic variant in a recessive disorder. No allelic phase data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 Moderate applies to protein length changes (in-frame indels or stop-loss). This intronic substitution does not alter protein length. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 Moderate applies to novel missense changes at a residue with a different pathogenic missense. This variant is intronic and not missense. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 Supporting applies to assumed de novo without confirmation. No such data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 applies to co-segregation with disease in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 Supporting applies to missense variants in a gene with low rate of benign missense. This is an intronic variant. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PMS2, PP3 Supporting applies to non-canonical splice site variants with SpliceAI delta ≥0.2. SpliceAI predicts delta 0.01. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 Supporting requires a highly specific phenotype or tumor profile. No tumor or clinical phenotype data are available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 Supporting applies when a reputable source classifies as pathogenic without evidence. The variant is reported as benign in ClinVar. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 Stand Alone applies for allele frequency ≥0.28% in controls. The variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines for PMS2, BS1 Strong applies for allele frequency 0.01–0.1%. The variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines for PMS2, BS2 Strong applies to co-occurrence in trans with a pathogenic variant in LS patients. No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 Strong applies to well-validated functional assays showing no damaging effect. No functional assays exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 Strong applies to lack of segregation in multiple affected. No segregation data available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 Supporting applies to missense in a gene where only truncating pathogenic variants. This is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 Supporting applies to observation in trans with a pathogenic variant in dominant disorder. No data. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 Supporting applies to in-frame deletions/insertions in repetitive region. Not applicable to this SNV. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines for PMS2, BP4 Supporting: "For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1." SpliceAI delta is 0.01. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 Supporting applies to variants found in a case with an alternate molecular basis for disease. No tumor or alternate molecular data. Therefore, BP5 is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, BP6 Supporting: "Reputable source reports benign but evidence not available." ClinVar lists this variant as Likely benign from three labs. Therefore, BP6 is applied at Supporting strength.
BP7 (Not Applied)
According to VCEP guidelines for PMS2, BP7 Supporting applies to intronic variants at or beyond −21/+7. Position −8 is within the splice region. Therefore, BP7 is not applied.