12-10418447-C-T

Position:

• chr12-10418447-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002261.3(KLRC3):​c.383G>A​(p.Cys128Tyr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLRC3 NM_002261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

Genes affected

KLRC3 (HGNC:6376): (killer cell lectin like receptor C3) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. KLRC3 is a member of the NKG2 group which are expressed primarily in natural killer (NK) cells and encodes a family of transmembrane proteins characterized by a type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. The NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ENSG00000255641 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC3	NM_002261.3	c.383G>A	p.Cys128Tyr	missense_variant	4/7	ENST00000396439.7	NP_002252.2
KLRC3	NM_007333.2	c.383G>A	p.Cys128Tyr	missense_variant	4/6		NP_031359.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC3	ENST00000396439.7	c.383G>A	p.Cys128Tyr	missense_variant	4/7	5	NM_002261.3	ENSP00000379716.3
KLRC3	ENST00000381903.2	c.383G>A	p.Cys128Tyr	missense_variant	4/6	1		ENSP00000371328.2
ENSG00000255641	ENST00000539033.1	c.383G>A	p.Cys128Tyr	missense_variant	4/7	1		ENSP00000437563.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.383G>A (p.C128Y) alteration is located in exon 4 (coding exon 4) of the KLRC3 gene. This alteration results from a G to A substitution at nucleotide position 383, causing the cysteine (C) at amino acid position 128 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.52	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	4.1	H;H;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.74
MutPred		0.83		Gain of catalytic residue at S127 (P = 5e-04);Gain of catalytic residue at S127 (P = 5e-04);Gain of catalytic residue at S127 (P = 5e-04);
MVP		0.34
MPC		1.1, 0.46
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.87
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-10571046;