Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000222.3(KIT):c.1638A>G(p.Lys546Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,613,900 control chromosomes in the GnomAD database, including 716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 33)

Exomes 𝑓: 0.027 ( 662 hom. )

Consequence

KIT
NM_000222.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.77

Publications

40 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 4-54727315-A-G is Benign according to our data. Variant chr4-54727315-A-G is described in ClinVar as Benign. ClinVar VariationId is 255569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0233 (3548/152338) while in subpopulation EAS AF = 0.0487 (253/5190). AF 95% confidence interval is 0.0438. There are 54 homozygotes in GnomAd4. There are 1723 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3548 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIT	NM_000222.3	MANE Select	c.1638A>G	p.Lys546Lys	synonymous	Exon 10 of 21	NP_000213.1
KIT	NM_001385284.1		c.1641A>G	p.Lys547Lys	synonymous	Exon 10 of 21	NP_001372213.1
KIT	NM_001385290.1		c.1641A>G	p.Lys547Lys	synonymous	Exon 10 of 21	NP_001372219.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIT	ENST00000288135.6	TSL:1 MANE Select	c.1638A>G	p.Lys546Lys	synonymous	Exon 10 of 21	ENSP00000288135.6
KIT	ENST00000412167.7	TSL:1	c.1629A>G	p.Lys543Lys	synonymous	Exon 10 of 21	ENSP00000390987.3
KIT	ENST00000687109.1		c.1641A>G	p.Lys547Lys	synonymous	Exon 10 of 21	ENSP00000509371.1

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3549

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00523

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0182

Gnomad ASJ

AF:

0.0755

Gnomad EAS

AF:

0.0484

Gnomad SAS

AF:

0.0333

Gnomad FIN

AF:

0.0163

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0307

Gnomad OTH

AF:

0.0272

GnomAD2 exomes

AF:

0.0275

AC:

6895

AN:

251176

AF XY:

0.0286

show subpopulations

Gnomad AFR exome

AF:

0.00547

Gnomad AMR exome

AF:

0.00900

Gnomad ASJ exome

AF:

0.0669

Gnomad EAS exome

AF:

0.0492

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0283

GnomAD4 exome

AF:

0.0275

AC:

40150

AN:

1461562

Hom.:

662

Cov.:

AF XY:

0.0282

AC XY:

20537

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00370

AC:

124

AN:

33470

American (AMR)

AF:

0.0102

AC:

457

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0681

AC:

1779

AN:

26130

East Asian (EAS)

AF:

0.0392

AC:

1556

AN:

39694

South Asian (SAS)

AF:

0.0332

AC:

2867

AN:

86244

European-Finnish (FIN)

AF:

0.0175

AC:

934

AN:

53416

Middle Eastern (MID)

AF:

0.0319

AC:

184

AN:

5768

European-Non Finnish (NFE)

AF:

0.0275

AC:

30549

AN:

1111732

Other (OTH)

AF:

0.0282

AC:

1700

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2137

4273

6410

8546

10683

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1112

2224

3336

4448

5560

<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:

0.0233

AC:

3548

AN:

152338

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1723

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00519

AC:

216

AN:

41586

American (AMR)

AF:

0.0182

AC:

278

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

262

AN:

3468

East Asian (EAS)

AF:

0.0487

AC:

253

AN:

5190

South Asian (SAS)

AF:

0.0330

AC:

159

AN:

4824

European-Finnish (FIN)

AF:

0.0163

AC:

173

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0307

AC:

2086

AN:

68030

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

179

357

536

714

893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0305

Hom.:

Bravo

AF:

0.0227

Asia WGS

AF:

0.0460

AC:

160

AN:

3478

EpiCase

AF:

0.0326

EpiControl

AF:

0.0281

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gastrointestinal stromal tumor (3)

not specified (3)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Mastocytosis (1)

Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.3

(source)

DANN

Benign

0.42

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over