Genetic Variant KIT:p.Pro949Pro (chr4-54738473-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000222.3(KIT):c.2847C>T(p.Pro949Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,614,022 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P949P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 83 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 45 hom. )

Consequence

KIT
NM_000222.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.569

Publications

8 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: 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

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=-0.69).

BP6

Variant 4-54738473-C-T is Benign according to our data. Variant chr4-54738473-C-T is described in ClinVar as Benign. ClinVar VariationId is 348955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.569 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

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	UniProt
KIT	NM_000222.3	MANE Select	c.2847C>T	p.Pro949Pro	synonymous	Exon 21 of 21	NP_000213.1	P10721-1
KIT	NM_001385284.1		c.2850C>T	p.Pro950Pro	synonymous	Exon 21 of 21	NP_001372213.1	A0A8I5KS03
KIT	NM_001385290.1		c.2847C>T	p.Pro949Pro	synonymous	Exon 21 of 21	NP_001372219.1	A0A8I5QKP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIT	ENST00000288135.6	TSL:1 MANE Select	c.2847C>T	p.Pro949Pro	synonymous	Exon 21 of 21	ENSP00000288135.6	P10721-1
KIT	ENST00000412167.7	TSL:1	c.2835C>T	p.Pro945Pro	synonymous	Exon 21 of 21	ENSP00000390987.3	A0A8J8Z860
KIT	ENST00000687109.1		c.2850C>T	p.Pro950Pro	synonymous	Exon 21 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2577

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0575

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00838

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00484

AC:

1214

AN:

251080

AF XY:

0.00343

show subpopulations

Gnomad AFR exome

AF:

0.0588

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000653

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00199

AC:

2905

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1238

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0523

AC:

1752

AN:

33472

American (AMR)

AF:

0.00470

AC:

210

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000558

AC:

620

AN:

1111944

Other (OTH)

AF:

0.00447

AC:

270

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.0171

AC:

2606

AN:

152216

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1235

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0581

AC:

2411

AN:

41516

American (AMR)

AF:

0.00837

AC:

128

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68024

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

127

255

382

510

637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00965

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Gastrointestinal stromal tumor (3)

Hereditary cancer-predisposing syndrome (1)

KIT-related disorder (1)

Mastocytosis (1)

Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.0

(source)

DANN

Benign

0.51

PhyloP100

-0.57

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over