NM_000222.3:c.2152A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000222.3(KIT):c.2152A>G(p.Thr718Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,612,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. T718T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 1 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.816

Publications

1 publications found

Variant links:

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

KIT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP2

Missense variant in the KIT gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.5806 (below the threshold of 3.09). Trascript score misZ: 4.1549 (above the threshold of 3.09). GenCC associations: The gene is linked to cutaneous mastocytosis, gastrointestinal stromal tumor, mastocytosis, piebaldism.

BP4

Computational evidence support a benign effect (MetaRNN=0.009217501).

BP6

Variant 4-54731338-A-G is Benign according to our data. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54731338-A-G is described in CliVar as Likely_benign. Clinvar id is 458908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000046 (7/152290) while in subpopulation SAS AF = 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3 link	c.2152A>G	p.Thr718Ala	missense_variant	Exon 15 of 21	ENST00000288135.6	NP_000213.1	P10721-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6 link	c.2152A>G	p.Thr718Ala	missense_variant	Exon 15 of 21	1	NM_000222.3	ENSP00000288135.6		P10721-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

250924

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000973

AC:

142

AN:

1460010

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

105

AN XY:

726478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00155

AC:

134

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110458

Other (OTH)

AF:

0.000116

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIT: BP4, BS1 -

Gastrointestinal stromal tumor

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jan 08, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.50

CADD

Benign

6.4

(source)

DANN

Benign

0.42

DEOGEN2

Uncertain

0.44

.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.65

.;N

PhyloP100

0.82

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.093

Sift

Benign

0.73

T;T

Sift4G

Benign

0.78

T;T

Polyphen

0.0010

B;B

Vest4

0.16

MutPred

0.46

.;Gain of glycosylation at Y721 (P = 0);

MVP

0.47

MPC

0.44

ClinPred

0.0070

GERP RS

3.2

Varity_R

0.16

gMVP

0.45

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over