KRAS c.451-22G>T, p.?
NM_033360.4:c.451-22G>T
Variant of Uncertain Significance (VUS)
This intronic KRAS variant shows no predicted impact on splicing or function (BP4, BP7). No pathogenic evidence is present. Two supporting benign criteria lead to a Likely Benign classification.
ACMG/AMP Criteria Applied
BP4
BP7
Genetic Information
Gene & Transcript Details
Gene
KRAS
Transcript
NM_033360.2
Total Exons
6
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_033360.4 | Alternative | 6 exons | Reverse |
| NM_033360.3 | Alternative | 6 exons | Reverse |
Variant Details
HGVS Notation
NM_033360.4:c.451-22G>T
Protein Change
?
Location
Exon 4
(Exon 4 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.451-22G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000881%
Very Rare
Global: 0.000398%
European (non-Finnish): 0.000881%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250952Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/250952 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000881%, 1/113450 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.85
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Not Applied) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 requires assumed de novo occurrence without confirmation. No parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation data in affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation with disease. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is intronic. Therefore, this criterion is not applied.
BP4
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
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.