KRAS c.112-12C>T, p.?
NM_033360.4:c.112-12C>T
Likely Benign
The intronic variant c.112-12C>T in KRAS has no evidence of functional impact, is present at very low frequency in controls, and is reported as benign in ClinVar. Computational and splicing predictions support a benign effect (BP4, BP7), and a reputable source classifies it as benign (BP6). No pathogenic criteria apply, supporting a final classification of Likely Benign.
ACMG/AMP Criteria Applied
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_033360.4:c.112-12C>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
Loading genome browser...
HGVS InputNM_033360:c.112-12C>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.00279%
Rare
Highest in Population
European (non-Finnish)
0.00618%
Rare
Global: 0.00279%
European (non-Finnish): 0.00618%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250686Alt: 7Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00279%, 7/250686 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00618%, 7/113338 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Variant summary: KRAS c.112-12C>T alters a conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.2e-05 in 1612992 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in KRAS causing Noonan Syndrome phenotype (1.3e-05). c.112-12C>T has been reported in the literature in individuals affected with Noonan Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 1065170). Based on the evidence outlined above, the variant was classified as benign.
Clinical Statement
This variant has been reported in ClinVar as Benign (1 clinical laboratories) and 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: 3.87
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 an intronic change at position -12, not affecting the canonical splice site. Therefore, this criterion is not applied because the variant is not a null variant in a canonical splice site.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG 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 no amino acid change (intronic). Therefore, this criterion is not applied because there is no amino acid change.
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 data. Therefore, this criterion is not applied due to lack of de novo evidence.
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 because functional evidence is missing.
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 proband frequency data. Therefore, this criterion is not applied due to lack of case-control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP KRAS 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 intronic and not within these domains. Therefore, this criterion is not applied because the variant is outside critical functional domains.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP KRAS guidelines, the rule for PM2 is: "Supporting Strength: Supporting The variant must be absent from controls (gnomAD)." The evidence for this variant shows a gnomAD MAF of 0.00279%. Therefore, this criterion is not applied because the variant is present in controls.
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 or trans data. Therefore, this criterion is not applied due to lack of recessive/trans data.
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 or stop-loss variants." The evidence for this variant shows no protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP KRAS guidelines, the rule for PM5 is: "Moderate Strength: 1 [likely] pathogenic residue change at the same codon." The evidence for this variant shows no missense codon change. 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, but without confirmation of paternity and 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 KRAS guidelines, the rule for PP1 is: "Segregation 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 VCEP KRAS guidelines, the rule for PP2 is: "Missense variants in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP KRAS 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 SpliceAI predicts minimal impact and no deleterious computational signal. Therefore, this criterion is not applied because computational predictions do not support a deleterious effect aligned with the disease mechanism.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a 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 the variant as pathogenic, but the evidence is not available." The evidence for this variant shows no reputable source calling it pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP KRAS guidelines, the rule for BA1 is: "Stand Alone Strength: GnomAD filtering allele frequency ≥0.05%." The evidence for this variant shows a MAF of 0.00279%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP KRAS guidelines, the rule for BS1 is: "Strong Strength: GnomAD filtering allele frequency ≥0.025%." The evidence for this variant shows a MAF of 0.00279%, below threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a recessive (≥2 observations) or dominant (≥1 observation)." The evidence for this variant shows no healthy individual data. 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 on protein function or splicing." 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 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 KRAS guidelines, the rule for BP1 is: "Supporting Strength: Truncating variant in gene where only gain-of-function is disease mechanism." The evidence for this variant shows it is intronic. 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 dominant disorder or in cis with a pathogenic variant." 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 rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function." The evidence for this variant shows no in-frame indel in a repetitive region. 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 impact on splicing (score 0.01) and other in silico tools do not indicate deleterious effects. Therefore, this criterion is applied at Supporting strength because computational predictions support a benign 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 case data. 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, but the evidence is not available to the laboratory." The evidence for this variant shows ClinVar reports it as Benign (1 laboratory) and Likely benign (1 laboratory). Therefore, this criterion is applied at Supporting strength because a reputable source classifies it as benign.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous or intronic variant (except canonical splice sites) for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved." The evidence for this variant shows it is intronic at -12, SpliceAI predicts no impact, and computational conservation metrics do not indicate high conservation. Therefore, this criterion is applied at Supporting strength.