KRAS c.336C>T, p.Val112=
NM_033360.4:c.336C>T
Likely Benign
This synonymous KRAS variant is absent from population databases, predicted benign by computational tools with no splicing impact, and reported as likely benign by a reputable source. The application of one supporting PM2 and two supporting benign criteria (BP6, BP7) yields a final classification of Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP6
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.336C>T
Protein Change
V112=
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.336C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories).
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: 0.91
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PVS1 rule: a null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where loss of function is a known mechanism of disease. The evidence for this variant shows it is a synonymous (silent) change with no alteration to protein sequence. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule (Strong): same amino acid change as a previously established pathogenic variant regardless of nucleotide change. The evidence for this variant shows no amino acid change (V112=). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the PS2 rule (Very Strong/Strong/Moderate) applies to confirmed or assumed de novo variants. The evidence for this variant shows no available de novo inheritance data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the PS3 rule (Moderate/Supporting) requires well-validated functional studies demonstrating a damaging effect. The evidence for this variant shows no functional characterization. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the PS4 rule (Strong/Moderate/Supporting) requires statistical evidence of enrichment in affected individuals. The evidence for this variant shows no case-control or cohort data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the PM1 rule (Moderate) applies to variants in critical functional domains (P-loop AA10-17, SW1 AA25-40, SW2 AA57-64, SAK AA145-156). The evidence for this variant at amino acid 112 lies outside these regions. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2 rule (Supporting): variant must be absent from controls (gnomAD). The evidence for this variant shows absence from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM3 rule (Moderate) applies to recessive conditions requiring phase-confirmed observations in trans. The evidence for this variant shows no relevant recessive inheritance context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the PM4 rule (Moderate) applies to in-frame insertions/deletions or stop-loss variants. The evidence for this variant shows a synonymous change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the PM5 rule (Strong/Moderate) applies to novel missense changes at codons with established pathogenic missense changes. The evidence for this variant shows no amino acid change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the PM6 rule (Strong/Moderate/Supporting) applies to assumed de novo variants without confirmation. The evidence for this variant shows no inheritance data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the PP1 rule (Supporting/Moderate/Strong) requires segregation of the variant with disease in multiple affected family members. The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule (Supporting) applies to missense variants in genes with low rate of benign missense variation. The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the PP3 rule (Supporting) applies to missense variants with REVEL ≥0.7 or impactful splicing predictions. The evidence for this variant shows neither missense effect nor significant splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP4 rule (Supporting) requires a highly specific phenotype or family history. 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 PP5 rule (Supporting) applies when a reputable source reports a variant as pathogenic but evidence is unavailable. The evidence for this variant shows a reputable source reporting likely benign (ClinVar), not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the BA1 rule (Stand Alone) requires allele frequency ≥0.05% in gnomAD. The evidence for this variant shows absence in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the BS1 rule (Strong) requires allele frequency ≥0.025% in gnomAD. The evidence for this variant shows absence in population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the BS2 rule (Strong/Supporting) applies when observed in healthy adult individuals. The evidence for this variant shows no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS3 rule (Strong) requires well-validated functional studies showing no damaging effect. The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS4 rule (Strong) applies when there 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 BP1 rule (Supporting) applies to truncating variants in genes without LOF correlation. The evidence for this variant shows a synonymous change. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP2 rule (Supporting/Moderate/Strong) applies when observed in trans with a pathogenic variant for a dominant disorder or cis for a recessive disorder. The evidence for this variant shows no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP3 rule (Supporting) applies to in-frame indels in repetitive regions. The evidence for this variant shows a single-nucleotide substitution. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the BP4 rule (Supporting) is specific to missense variants with REVEL ≤0.3. The evidence for this variant shows a synonymous change. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP5 rule (Supporting/Moderate/Strong) applies when a variant is found in a case with an alternate molecular basis for disease. The evidence for this variant shows none. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the BP6 rule (Supporting): reputable source reports variant as benign but evidence unavailable. The evidence for this variant shows ClinVar reports it as Likely Benign with no underlying data. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the BP7 rule (Supporting): a synonymous variant with no predicted splice impact and not highly conserved. The evidence for this variant shows SpliceAI predicts no splicing impact (score 0.02) and no amino acid change. Therefore, this criterion is applied at Supporting strength.