NM_000222.3:c.1231+6692C>T

Variant names:

• chr4-54716231-C-T
• rs17084687
• NM_000222.3:c.1231+6692C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000222.3(KIT):​c.1231+6692C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 151,988 control chromosomes in the GnomAD database, including 1,344 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1344 hom., cov: 32)
• Consequence: KIT NM_000222.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143
• Publications: 3 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• piebaldism

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.1231+6692C>T		intron_variant	Intron 7 of 20	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.1231+6692C>T		intron_variant	Intron 7 of 20	1	NM_000222.3	ENSP00000288135.6

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16236 AN: 151870 Hom.: 1336 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0974

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.107 AC: 16283 AN: 151988 Hom.: 1344 Cov.: 32 AF XY: 0.109 AC XY: 8075 AN XY: 74268

African (AFR) AF: 0.211 AC: 8748 AN: 41436

American (AMR) AF: 0.117 AC: 1789 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 230 AN: 3470

East Asian (EAS) AF: 0.268 AC: 1385 AN: 5162

South Asian (SAS) AF: 0.0646 AC: 310 AN: 4796

European-Finnish (FIN) AF: 0.0392 AC: 414 AN: 10548

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3147 AN: 68006

Other (OTH) AF: 0.0969 AC: 204 AN: 2106

Alfa AF: 0.0654 Hom.: 727

Bravo AF: 0.119

Asia WGS AF: 0.153 AC: 534 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.8
DANN	Benign	0.67
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs17084687; hg19: chr4-55582397;