Variant 12-10431157-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002260.4(KLRC2):c.656G>A(p.Cys219Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,547,480 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000021 ( 5 hom. )

Consequence

KLRC2
NM_002260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

KLRC2 (HGNC:6375): (killer cell lectin like receptor C2) 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. The group, designated KLRC (NKG2) 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 KLRC (NKG2) gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. KLRC2 alternative splice variants have been described but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

KLRC2 links:

ENSG00000255641 (HGNC:):

ENSG00000255641 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC2	NM_002260.4 linkuse as main transcript	c.656G>A	p.Cys219Tyr	missense_variant	6/6	ENST00000381902.7	NP_002251.2	P26717

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC2	ENST00000381902.7 linkuse as main transcript	c.656G>A	p.Cys219Tyr	missense_variant	6/6	1	NM_002260.4	ENSP00000371327.2		P26717
ENSG00000255641	ENST00000539033.1 linkuse as main transcript	c.331+3329G>A		intron_variant		1		ENSP00000437563.1		F5H6K3

Frequencies

GnomAD3 genomes

AF:

0.00000703

AC:

AN:

142196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000219

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000333

AC:

AN:

240454

Hom.:

AF XY:

0.0000538

AC XY:

AN XY:

130230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000267

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1405284

Hom.:

Cov.:

AF XY:

0.0000314

AC XY:

AN XY:

699798

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000355

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000703

AC:

AN:

142196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69166

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000219

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000419

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

The c.656G>A (p.C219Y) alteration is located in exon 6 (coding exon 6) of the KLRC2 gene. This alteration results from a G to A substitution at nucleotide position 656, causing the cysteine (C) at amino acid position 219 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

0.79

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.94

Eigen

Benign

0.0041

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.019

LIST_S2

Uncertain

0.86

.;D;D;D

M_CAP

Benign

0.0016

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Benign

-0.89

PROVEAN

Pathogenic

-8.6

D;.;D;D

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Vest4

0.54

MutPred

0.82

Gain of catalytic residue at I224 (P = 0.0011);.;Gain of catalytic residue at I224 (P = 0.0011);.;

MVP

0.60

MPC

1.4

ClinPred

0.99

GERP RS

1.3

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over