NM_000222.3:c.2466T>G

Variant names:

• chr4-54733174-T-G
• rs121913514
• NM_000222.3:c.2466T>G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1_Moderate PS3 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000222.3(KIT):​c.2466T>G​(p.Asn822Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004374770: Experimental studies have shown that this missense change affects KIT function (PMID:15790786, 17699867, 20890793, 21262832, 28506695)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N822I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.53
• Publications: 309 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS1: Transcript NM_000222.3 (KIT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004374770: Experimental studies have shown that this missense change affects KIT function (PMID: 15790786, 17699867, 20890793, 21262832, 28506695).; SCV005333426: Published functional studies demonstrate a damaging effect: increased cellular proliferation and phosphorylation in vitro and hyperplasia of intestinal cells on a mouse model (Omori et al., 2017; Klein-Rodewald et al., 2022)
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000222.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-54733173-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375930.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 mastocytosis, piebaldism, gastrointestinal stromal tumor, cutaneous mastocytosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 4-54733174-T-G is Pathogenic according to our data. Variant chr4-54733174-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	NM_000222.3	MANE Select	c.2466T>G	p.Asn822Lys	missense	Exon 17 of 21	NP_000213.1	P10721-1
	KIT	NM_001385284.1		c.2469T>G	p.Asn823Lys	missense	Exon 17 of 21	NP_001372213.1	A0A8I5KS03
	KIT	NM_001385290.1		c.2466T>G	p.Asn822Lys	missense	Exon 17 of 21	NP_001372219.1	A0A8I5QKP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	ENST00000288135.6	TSL:1 MANE Select	c.2466T>G	p.Asn822Lys	missense	Exon 17 of 21	ENSP00000288135.6	P10721-1
	KIT	ENST00000412167.7	TSL:1	c.2454T>G	p.Asn818Lys	missense	Exon 17 of 21	ENSP00000390987.3	A0A8J8Z860
	KIT	ENST00000687109.1		c.2469T>G	p.Asn823Lys	missense	Exon 17 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Gastrointestinal stromal tumor (1)
-	-	-	Germinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.023	D
MutationAssessor	Benign	0.80	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.59		Gain of MoRF binding (P = 0.0307)
MVP		0.91
MPC		1.4
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.93
gMVP		0.76
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.18		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: rs121913514; hg19: chr4-55599340; COSMIC: COSV55387147;