KRAS c.24A>G, p.Val8=
NM_033360.2:c.24A>G
COSM507
Population Frequency
0.0254%
Common
ClinVar Classification
Likely Benign
1 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
2 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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_033360.2:c.24A>G
Protein Change
V8=
Location
Exon 2
(Exon 2 of 6)
5'
Exon Structure (6 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM507
Variant interpretation based on transcript NM_033360.2
Clinical Evidence
Global Frequency
0.0254%
Low Frequency
Highest in Population
European (non-Finnish)
0.051%
Common
Global: 0.0254%
European (non-Finnish): 0.051%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 279964
Alt: 71
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0254%, 71/279964 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.051%, 65/127570 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Likely Benign
Based on 14 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
1 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely benign by ClinGen RASopathy Variant Curation Expert Panel expert panel.
Expert Panel Reviews
Likely benign
ClinGen RASopathy Variant Curation Expert Panel
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
Functional Studies
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variants (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease are assigned PVS1.' The evidence for this variant shows: it is a synonymous variant (V8=) that does not create a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: it is synonymous with no amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no de novo origin data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well‐established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with controls.' The evidence for this variant shows: no case-control or case series data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Applicable only to critical and well-established functional domains (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]).' The evidence for this variant shows: it is at codon 8, outside these domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: 'The variant must be absent from controls (gnomAD).' The evidence for this variant shows: it is observed in gnomAD at MAF=0.0254%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no in trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region.' The evidence for this variant shows: it is a synonymous substitution with no length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Different pathogenic residue changes at the same codon.' The evidence for this variant shows: it is synonymous and does not alter the amino acid. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation.' The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'For missense variants, REVEL ≥0.7; for splicing impact, predicted outcome must match disease mechanism.' The evidence for this variant shows: it is synonymous and REVEL/splicing predictions do not indicate pathogenicity. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with single genetic etiology.' The evidence for this variant shows: no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic when evidence is unavailable for independent evaluation.' The evidence for this variant shows: no reputable source reports pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'GnomAD filtering allele frequency ≥0.05% qualifies as stand-alone benign.' The evidence for this variant shows: global MAF=0.0254% <0.05%. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: 'GnomAD filtering allele frequency ≥0.025% qualifies as strong benign.' The evidence for this variant shows: global MAF=0.0254%, which meets the threshold. Therefore, this criterion is applied at Strong strength.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a recessive disorder or in controls inconsistent with disease.' The evidence for this variant shows: no data in healthy controls beyond population frequency. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies show no damaging effect.' The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Truncating variant in a gene where loss-of-function is not a mechanism.' The evidence for this variant shows: it is synonymous, not truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene; or observed in cis with another pathogenic variant.' The evidence for this variant shows: no in cis or in trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: it is a single-base substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: SpliceAI predicts no splice impact (score=0.02) and in silico tools do not predict pathogenicity. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such context. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source recently reports variant as benign without available evidence.' The evidence for this variant shows: multiple ClinVar submissions and ClinGen expert panel report it as benign/likely benign. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: 'A synonymous variant for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved.' The evidence for this variant shows: it is synonymous and SpliceAI predicts no splice impact. Therefore, this criterion is applied at Supporting strength.