NM_000222.3:c.2394C>T

Variant names:

• chr4-54733102-C-T
• rs55789615
• NM_000222.3:c.2394C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000222.3(KIT):​c.2394C>T​(p.Ile798Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,611,398 control chromosomes in the GnomAD database, including 795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I798I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (65 hom., cov: 32)
  • Exomes 𝑓: 0.029 (730 hom.)
• Consequence: KIT NM_000222.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.411
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• piebaldism

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• cutaneous mastocytosis

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mastocytosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 4-54733102-C-T is Benign according to our data. Variant chr4-54733102-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.411 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0208 (3164/152232) while in subpopulation NFE AF = 0.0321 (2182/68002). AF 95% confidence interval is 0.031. There are 65 homozygotes in GnomAd4. There are 1461 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3164 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000222.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	NM_000222.3	MANE Select	c.2394C>T	p.Ile798Ile	synonymous	Exon 17 of 21	NP_000213.1	P10721-1
	KIT	NM_001385284.1		c.2397C>T	p.Ile799Ile	synonymous	Exon 17 of 21	NP_001372213.1	A0A8I5KS03
	KIT	NM_001385290.1		c.2394C>T	p.Ile798Ile	synonymous	Exon 17 of 21	NP_001372219.1	A0A8I5QKP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	ENST00000288135.6	TSL:1 MANE Select	c.2394C>T	p.Ile798Ile	synonymous	Exon 17 of 21	ENSP00000288135.6	P10721-1
	KIT	ENST00000412167.7	TSL:1	c.2382C>T	p.Ile794Ile	synonymous	Exon 17 of 21	ENSP00000390987.3	A0A8J8Z860
	KIT	ENST00000687109.1		c.2397C>T	p.Ile799Ile	synonymous	Exon 17 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3167 AN: 152114 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0321

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0204 AC: 5127 AN: 251082 AF XY: 0.0210

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0290 AC: 42272 AN: 1459166 Hom.: 730 Cov.: 30 AF XY: 0.0287 AC XY: 20808 AN XY: 726060

African (AFR) AF: 0.00452 AC: 151 AN: 33396

American (AMR) AF: 0.0111 AC: 497 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 540 AN: 26082

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39634

South Asian (SAS) AF: 0.0108 AC: 933 AN: 86204

European-Finnish (FIN) AF: 0.0139 AC: 743 AN: 53358

Middle Eastern (MID) AF: 0.0269 AC: 155 AN: 5758

European-Non Finnish (NFE) AF: 0.0341 AC: 37829 AN: 1109764

Other (OTH) AF: 0.0236 AC: 1422 AN: 60264

GnomAD4 genome AF: 0.0208 AC: 3164 AN: 152232 Hom.: 65 Cov.: 32 AF XY: 0.0196 AC XY: 1461 AN XY: 74436

African (AFR) AF: 0.00595 AC: 247 AN: 41544

American (AMR) AF: 0.0187 AC: 285 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4820

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0321 AC: 2182 AN: 68002

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0278 Hom.: 39

Bravo AF: 0.0217

Asia WGS AF: 0.00318 AC: 11 AN: 3476

EpiCase AF: 0.0326

EpiControl AF: 0.0353

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Gastrointestinal stromal tumor (4)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not specified (3)
-	-	1	Mastocytosis (1)
-	-	1	Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.8
DANN	Benign	0.75
PhyloP100		0.41
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55789615; hg19: chr4-55599268; COSMIC: COSV55386746;