Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_033360.2 | Alternative | 5436 nt | 182–751 |
| NM_033360.4 | Alternative | 5430 nt | 191–760 |
| NM_033360.3 | Alternative | 5889 nt | 193–762 |
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 | 8 bp |
| Donor Loss (DL) | 0.0 | -48 bp |
| Acceptor Gain (AG) | 0.06 | -22 bp |
| Donor Gain (DG) | 0.1 | -145 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, PVS1 pertains to null variants in a gene where loss of function is a known mechanism. The evidence shows NM_033360.4:c.451-22G>T is an intronic non-canonical splice region variant and KRAS disease mechanism is gain-of-function. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 requires the same amino acid change as a known pathogenic variant. The evidence shows this variant is intronic (no amino acid change). Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 requires de novo occurrence with confirmed maternity and paternity. Parental data are not available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires well-validated functional studies demonstrating a deleterious effect. No functional assays for this variant are available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires case-level or case-control data showing increased prevalence in affected individuals. No such data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to missense variants in defined functional domains. This is an intronic variant outside canonical splice sites. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, PM2 (Supporting) requires absence from controls in gnomAD. The variant is present in gnomAD at MAF=0.000398%. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to detected in trans for recessive disorders. Not applicable for this dominant gain-of-function gene. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, PM4 applies to protein length changes like in-frame indels. This is intronic with no coding effect. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 applies to novel missense changes at a codon with known pathogenic missense variants. This is intronic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 requires assumed de novo occurrence without confirmation. No parental data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires segregation data in affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in a gene with low rate of benign missense. This is intronic. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 (Supporting) requires REVEL ≥0.7 for missense or splicing predictions matching mechanism. SpliceAI predicts no significant impact (score ≤0.10). Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 requires a specific phenotype highly specific for this gene. No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 requires a reputable source classifying the variant as pathogenic. The variant is not in ClinVar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 requires allele frequency ≥0.05% in gnomAD. The variant frequency is 0.000398%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 requires allele frequency ≥0.025% in gnomAD. The variant frequency is 0.000398%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 requires observation in healthy adults for fully penetrant disorders. No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 requires well-established functional studies showing no deleterious effect. No functional data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 requires lack of segregation with disease. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1 applies to truncating variants in a gain-of-function gene. This is intronic, not truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 requires observation in cis with a pathogenic variant. No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is intronic. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 (Supporting) applies when multiple computational lines suggest no impact. SpliceAI score 0.10 and CADD 3.85 indicate no impact on splicing or function. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 requires an alternative benign explanation in a patient. No such data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 requires a reputable source classifying the variant as benign without evidence. The variant is not in any database. Therefore, this criterion is not applied.
BP7 (Supporting)
According to VCEP guidelines, BP7 (Supporting) applies to intronic variants outside canonical splice sites with splicing predictions showing no impact. SpliceAI prediction is minimal. Therefore, this criterion is applied at Supporting strength.