Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
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 | 13 bp |
| Donor Loss (DL) | 0.0 | 36 bp |
| Acceptor Gain (AG) | 0.71 | 0 bp |
| Donor Gain (DG) | 0.0 | -227 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to variants at the canonical splice positions (IVS±1 or IVS±2) or causing a null effect by nonsense/frameshift. This variant is at c.793-11, a non-canonical splice position and does not introduce a premature stop. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. This intronic duplication does not encode a missense change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with parental testing. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires validated functional assay evidence demonstrating 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 such data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 applies to variants in mutational hot spots or critical functional domains. This variant lies outside known hotspots/domains. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2_Supporting applies to variants absent or extremely rare (<1 in 50,000 alleles) in gnomAD v4. This variant is absent from gnomAD (MAF=0). Therefore, PM2 is applied at Supporting strength because it is absent from control databases.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to recessive disorders when a variant is observed in trans with a pathogenic variant. Lynch syndrome is dominant, and no trans data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels. The consequence of this intronic duplication on the protein is unknown. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where a different pathogenic missense change is established. This is an intronic duplication. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without parental confirmation. No de novo evidence is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 requires segregation data in affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. This is an intronic variant. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines, PP3_Supporting applies for predicted splice defects at non-canonical sites using SpliceAI with a delta score ≥0.2. SpliceAI predicts an acceptor gain with a score of 0.71. Therefore, PP3 is applied at Supporting strength because in silico tools predict a moderate splicing impact.
PP4 (Not Applied)
According to VCEP guidelines, PP4 requires tumor phenotype data (e.g., MSI-H or loss of MMR expression) consistent with the variant. No tumor data are available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies to assertions from reputable databases without evidence. No such assertions exist. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 requires allele frequency ≥0.1% in controls. This variant has MAF=0. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 requires allele frequency ≥0.01% and <0.1%. This variant has MAF=0. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 requires observation in trans with a pathogenic variant in unaffected individuals. No co-occurrence data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional assays demonstrating no impact. No functional data exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires lack of segregation in multiple affected family members. No segregation data exist. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when a variant is observed in cis with a pathogenic variant. No such data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is an intronic duplication; its repeat context is unknown. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 applies when SpliceAI predicts no splicing impact (delta ≤0.1). SpliceAI score is 0.71 indicating impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines, BP5 requires tumor phenotypes inconsistent with the gene. No tumor data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 requires a benign assertion from a reputable source. No such assertion exists. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to intronic variants at or beyond –21 from the exon. This variant is at –11, within the splice region. Therefore, BP7 is not applied.