KRAS c.-9C>T, p.?
NM_033360.2:c.-9C>T
Likely Benign
This non-coding KRAS variant is very rare (PM2_Supporting) and has multiple computational and reputable source benign evidence (BP4, BP6, BP7 all Supporting), supporting a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
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_033360.2:c.-9C>T
Protein Change
?
Location
Exon 2
(Exon 2 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.-9C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00596%
Rare
Highest in Population
Remaining individuals
0.0172%
Low Frequency
Global: 0.00596%
Remaining individuals: 0.0172%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 234942Alt: 14Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00596%, 14/234942 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0172%, 1/5822 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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
Functional Summary
The KRAS -9c>T variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.26
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "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 non-coding 5′UTR change and does not create a predicted null allele. Therefore, this criterion is not applied because the variant does not result in loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: "Strong—Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: it is non-coding and does not change an amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PS2: "Very Strong or Strong—De novo in patient with disease and no family history". The evidence for this variant shows: no de novo 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 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 VCEP guidelines for PS4: "Strong/Moderate/Supporting evidence from case-control data". The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1: "Moderate—Variant located in critical and well-established functional domains". The evidence for this variant shows: it is non-coding and outside known protein functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2: "Supporting—The variant must be absent from controls (gnomAD)". The evidence for this variant shows: MAF = 0.00596%, extremely low frequency in controls meeting absence from controls threshold. Therefore, this criterion is applied at Supporting strength because the variant is very rare in population databases.
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 recessive inheritance or trans data 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". The evidence for this variant shows: no in-frame indel or protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: "Strong/Moderate—Novel missense change at a residue where other pathogenic missense changes are known". The evidence for this variant shows: it is non-coding, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "De novo without confirmation of paternity/maternity". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1: "Supporting/Moderate/Strong—Segregation in 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 low rate of benign missense variation". The evidence for this variant shows: it is non-coding. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PP3: "Supporting—In silico predictions supportive of a deleterious effect for missense variants or splicing mechanism match". The evidence for this variant shows: SpliceAI predicts no splicing impact and missense thresholds not applicable. 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 a single genetic etiology". The evidence for this variant shows: no phenotype data provided. 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". The evidence for this variant shows: sources report it as benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: "Stand Alone—GnomAD filtering allele frequency ≥0.05%". The evidence for this variant shows: MAF = 0.00596% which is below 0.05%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Strong—GnomAD filtering allele frequency ≥0.025%". The evidence for this variant shows: MAF = 0.00596% which is below 0.025%. Therefore, this criterion is not applied.
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". 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 rule for BS3 is: "Well-established functional studies show no damaging effect". The evidence for this variant shows: no functional assays 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 family members". 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 for BP1: "Supporting—Truncating variant in gene where gain-of-function is mechanism". The evidence for this variant shows: it is non-coding, 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 cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans configuration. 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 repetitive regions". The evidence for this variant shows: 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 splicing impact and CADD score is low. Therefore, this criterion is applied at Supporting strength because in silico tools concordantly predict lack of effect.
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 reports variant as benign". The evidence for this variant shows: ClinVar entry from one clinical lab classifies it as Likely Benign. Therefore, this criterion is applied at Supporting strength because a credible source reports benign.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or non-coding variant for which splicing prediction algorithms predict no impact and nucleotide is not highly conserved". The evidence for this variant shows: it is non-coding with SpliceAI score of 0.01 and no conservation concern. Therefore, this criterion is applied at Supporting strength because computational splicing evidence indicates no effect.