rs779103998
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_000222.3(KIT):c.2837G>A(p.Arg946Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. R946L) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.2837G>A | p.Arg946Gln | missense_variant | 21/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.2837G>A | p.Arg946Gln | missense_variant | 21/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250940Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135686
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727220
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 946 of the KIT protein (p.Arg946Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 409766). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at