4-54727442-G-C

Position:

• chr4-54727442-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000222.3(KIT):​c.1674G>C​(p.Lys558Asn) 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K558K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 1.48

Genes affected

KIT (HGNC:6342): (KIT proto-oncogene, receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase. This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. The canonical form of this glycosylated transmembrane protein has an N-terminal extracellular region with five immunoglobulin-like domains, a transmembrane region, and an intracellular tyrosine kinase domain at the C-terminus. Upon activation by its cytokine ligand, stem cell factor (SCF), this protein phosphorylates multiple intracellular proteins that play a role in in the proliferation, differentiation, migration and apoptosis of many cell types and thereby plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and in mast cell development, migration and function. This protein can be a membrane-bound or soluble protein. Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous leukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2020]

KIT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIT. . Gene score misZ 2.5806 (greater than the threshold 3.09). Trascript score misZ 4.1549 (greater than threshold 3.09). GenCC has associacion of gene with piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3	c.1674G>C	p.Lys558Asn	missense_variant	11/21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.1674G>C	p.Lys558Asn	missense_variant	11/21	1	NM_000222.3	ENSP00000288135.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 14, 2023	The KIT c.1674G>C variant is classified as VARIANT OF UNCERTAIN SIGNIFICANCE (PM2, PP3, PM1_supporting) The KIT c.1674G>C variant is a single nucleotide change in exon 11/21 of the KIT gene, which is predicted to change the amino acid lysine at position 558 in the protein to asparagine. This variant is absent from population databases (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). In silico protein modelling of a similar variant (c.1674G>T; p.Lys558Asn) predicts that the KIT kinase module is constitutively activated when Lys558Asn combines with a secondary somatic KIT mutation (PM1_supporting). In one kindred reported in the literature, only 50% of family members with the detected p.Lys558Asn mutation presented with a phenotype, possibly pointing to its role as a predisposing cofactor (Meir et al, 2021; PMID:34338390). The variant has been reported in dbSNP (rs200375589). It has been reported as having uncertain clinical significance by another diagnostic laboratory (ClinVar Variation ID: 375910) and as a somatic variant (COSMIC: COSV55424409). It has not been reported in the HGMD or LOVD databases. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 14, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 558 of the KIT protein (p.Lys558Asn). This missense change has been observed in individuals with KIT-related conditions (PMID: 34338390; Invitae). 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. 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. ClinVar contains an entry for this variant (Variation ID: 375910). -
-, no assertion criteria provided	research	National Institute of Cancer Research, National Health Research Institutes	-	clinical data -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.58		.;Loss of methylation at K558 (P = 0.0121);
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.85
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200375589; hg19: chr4-55593608; COSMIC: COSV55424409; COSMIC: COSV55424409;