rs768847037

Variant names:

• chr4-54729448-C-G
• rs768847037
• NM_000222.3:c.2104C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-54729448-C-G
• chr4-54729448-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_000222.3(KIT):​c.2104C>G​(p.Leu702Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L702F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.92
• Publications: 2 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 -10 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=0.11713612).
• BP6: Variant 4-54729448-C-G is Benign according to our data. Variant chr4-54729448-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409779.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000958 (14/1461358) while in subpopulation AMR AF = 0.000201 (9/44706). AF 95% confidence interval is 0.000104. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	NM_000222.3	MANE Select	c.2104C>G	p.Leu702Val	missense	Exon 14 of 21	NP_000213.1
	KIT	NM_001385284.1		c.2107C>G	p.Leu703Val	missense	Exon 14 of 21	NP_001372213.1
	KIT	NM_001385290.1		c.2107C>G	p.Leu703Val	missense	Exon 14 of 21	NP_001372219.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	ENST00000288135.6	TSL:1 MANE Select	c.2104C>G	p.Leu702Val	missense	Exon 14 of 21	ENSP00000288135.6
	KIT	ENST00000412167.7	TSL:1	c.2095C>G	p.Leu699Val	missense	Exon 14 of 21	ENSP00000390987.3
	KIT	ENST00000687109.1		c.2107C>G	p.Leu703Val	missense	Exon 14 of 21	ENSP00000509371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250630 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

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: 0.00000958 AC: 14 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726958

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000201 AC: 9 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111734

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia;C0024899:Mastocytosis;C0080024:Piebaldism;C0153594:Malignant tumor of testis;C0238198:Gastrointestinal stromal tumor (1)
-	1	-	Gastrointestinal stromal tumor (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	KIT-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.23
Sift	Benign	0.45	T
Sift4G	Benign	0.51	T
Polyphen		0.17	B
Vest4		0.14
MutPred		0.34		Loss of sheet (P = 0.0181)
MVP		0.71
MPC		0.58
ClinPred		0.045	T
GERP RS		6.1
Varity_R		0.20
gMVP		0.51
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs768847037; hg19: chr4-55595614; COSMIC: COSV55388930;