KIT c.2394C>T, p.Ile798=
NM_000222.3:c.2394C>T
COSMIC ID: COSM1307
Likely Benign
Variant NM_000222.3:c.2394C>T (I798=) in KIT is classified as Benign based on stand-alone population frequency evidence (BA1), supported by multiple benign criteria (BP4, BP6, BP7).
ACMG/AMP Criteria Applied
BA1
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
KIT
Transcript
NM_000222.3
MANE Select
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000004.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000222.2 | RefSeq Select | 21 exons | Forward |
| NM_000222.1 | Alternative | 22 exons | Forward |
Variant Details
HGVS Notation
NM_000222.3:c.2394C>T
Protein Change
I798=
Location
Exon 17
(Exon 17 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM1307
Variant interpretation based on transcript NM_000222.3
Genome Browser
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HGVS InputNM_000222:c.2394C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
2.03%
Common
Highest in Population
European (non-Finnish)
3.29%
Common
Global: 2.03%
European (non-Finnish): 3.29%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282476Alt: 5748Homozygotes: 80
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 2.03%, 5748/282476 alleles, homozygotes = 80) and at a higher frequency in the European (non-Finnish) population (MAF= 3.29%, 4237/128928 alleles, homozygotes = 64). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Likely Benign
Based on 14 submitter reviews in ClinVar
Submitter Breakdown
3 LB
11 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as Likely benign (3 clinical laboratories).
COSMIC ID
COSM1307
Recurrence
27 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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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: 0.81
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: it is a synonymous variant (I798=) with no predicted loss of function. Therefore, this criterion is not applied because the variant does not create a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: it does not alter the amino acid (I798=) and there is no amino acid change. Therefore, this criterion is not applied because the variant does not change the protein sequence.
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: there is no information on de novo status or family history. 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 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 data are not available.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or cohort data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied due to absence of case prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: it is a synonymous variant outside of a known mutational hotspot. Therefore, this criterion is not applied because it does not affect a functional domain.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: it has a high allele frequency in gnomAD (overall 2.03%, NFE 3.29%). Therefore, this criterion is not applied because the variant is common in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no trans configuration data with a pathogenic variant. 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 or stop-loss variants'. The evidence for this variant shows: it is a synonymous substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: no amino acid change occurs. 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 assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG 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 and where missense variants are a common mechanism of disease'. 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 standard ACMG guidelines the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: in silico predictions are mixed but overall suggest no deleterious effect. Therefore, PP3 is not applied; instead BP4 is applied for benign computational evidence.
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, but without accessible evidence'. The evidence for this variant shows: reported as benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: MAF=2.03% overall and 3.29% in NFE with multiple homozygotes in gnomAD. Therefore, this criterion is applied at Stand Alone strength because the allele frequency far exceeds thresholds for pathogenicity.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: allele frequency meets BA1, which is stronger. Therefore, BS1 is not applied separately.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: population data include healthy individuals, but BA1 covers 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 functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies exist. 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 studies. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: it is synonymous. 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 dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no cis/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 known function'. The evidence for this variant shows: it is a single-nucleotide synonymous change, 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'. The evidence for this variant shows: CADD score of 0.81, SpliceAI scores of 0.00 predict no impact on splicing. Therefore, this criterion is applied at Supporting strength because in silico tools agree on benign impact.
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 case report with alternate molecular basis. 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, but without accessible evidence'. The evidence for this variant shows: ClinVar reports it as Benign (11 labs) and Likely benign (3 labs) without detailed evidence available. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is synonymous (I798=) and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength.