rs1057519708
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Very_StrongPM1PM2PP2PP3_ModeratePP5_Moderate
The NM_000222.3(KIT):c.1965T>A(p.Asn655Lys) 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N655S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000222.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.1965T>A | p.Asn655Lys | missense_variant | 13/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.1965T>A | p.Asn655Lys | missense_variant | 13/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Melanoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 655 of the KIT protein (p.Asn655Lys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KIT function (PMID: 17489795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 375923). This missense change has been observed in individuals with clinical features of KIT-related conditions (PMID: 17489795, 23106360, 33212994; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at