4-54733102-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 255571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54733102-C-T is described in Lovd as [Likely_benign]. Variant chr4-54733102-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.2394C>T	p.Ile798Ile	synonymous_variant	Exon 17 of 21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.2394C>T	p.Ile798Ile	synonymous_variant	Exon 17 of 21	1	NM_000222.3	ENSP00000288135.6

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

GnomAD3 exomes AF: 0.0204 AC: 5127 AN: 251082 Hom.: 73 AF XY: 0.0210 AC XY: 2849 AN XY: 135692

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 SAS exome AF: 0.00977

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

Gnomad4 AFR exome AF: 0.00452

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0236

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

Gnomad4 AFR AF: 0.00595

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0321

Gnomad4 OTH AF: 0.0189

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

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Aug 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

May 08, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 29, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 18, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, BP4, BP7 c.2394C>T, located in exon 17 of the KIT gene, is predicted to result in no amino acid change, p.(Ile798=) (BP7). This variant is found in 5369/267938 (77 homozygous), with a filter allele frequency of 1.94% at 99% confidence in the gnomAD v2.1.1 database (non-cancer data set)(BA1). The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, no relevant functional studies has been reported for this variant. This variant has been reported in the ClinVar database (4 likely benign, 10x benign). Based on currently available information, c.2394C>T is classified as a benign variant according to ACMG guidelines. -

Mastocytosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Piebaldism Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.8
DANN	Benign	0.75

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