rs121913514
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_ModeratePP5
The NM_000222.3(KIT):c.2466T>A(p.Asn822Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N822I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000222.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.2466T>A | p.Asn822Lys | missense_variant | 17/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.2466T>A | p.Asn822Lys | missense_variant | 17/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 01, 2018 | This sequence change replaces asparagine with lysine at codon 822 of the KIT protein (p.Asn822Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported as a germline variant in the literature in individuals with KIT-related disease. ClinVar contains an entry for this variant (Variation ID: 375931). Experimental studies have shown that this missense change results in constitutive phosphorylation of the KIT protein, increased cell proliferation in the presence of low concentration of growth factors, impaired apoptosis promotion, and resistance to low doses of imatinib (PMID: 14645423, 14695343, 17699867, 20890793, 28506695). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Melanoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Mar 07, 2017 | - - |
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Dec 26, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at