rs776681643
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_000222.3(KIT):c.2663G>A(p.Arg888Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R888W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000222.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.2663G>A | p.Arg888Gln | missense_variant | 19/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.2663G>A | p.Arg888Gln | missense_variant | 19/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251078Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135698
GnomAD4 exome AF: 0.0000944 AC: 138AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.0000963 AC XY: 70AN XY: 727210
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74328
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 888 of the KIT protein (p.Arg888Gln). This variant is present in population databases (rs776681643, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma, bone marrow failure, and colorectal cancer (PMID: 23020152, 29146883, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 409758). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect KIT function (PMID: 23020152). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including colon cancer and bone marrow failure (Bluteau et al., 2018; Huang et al., 2018); This variant is associated with the following publications: (PMID: 29146883, 29625052) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2018 | The p.R888Q variant (also known as c.2663G>A), located in coding exon 19 of the KIT gene, results from a G to A substitution at nucleotide position 2663. This variant has been detected in a familial melanoma patient (Bourillon A et al. Pigment Cell Melanoma Res, 2013 Jan;26:88-96). Functional analysis by these authors demonstrated reduced KIT activity for the p.R888Q allele compared to wild type protein; however, the difference wasn't significant. The arginine at codon 888 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at