Genetic Variant KLRC3:p.His195Arg (chr12-10416670-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002261.3(KLRC3):c.584A>G(p.His195Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,610,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KLRC3
NM_002261.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.916

Variant links:

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]

KLRC3 links:

ENSG00000255641 (HGNC:):

ENSG00000255641 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC3	NM_002261.3 link	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 7	ENST00000396439.7	NP_002252.2	Q07444-1
KLRC3	NM_007333.2 link	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 6		NP_031359.2	Q07444-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLRC3	ENST00000396439.7 link	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 7	5	NM_002261.3	ENSP00000379716.3	Q07444-1
KLRC3	ENST00000381903.2 link	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 6	1		ENSP00000371328.2	Q07444-2
ENSG00000255641	ENST00000539033.1 link	c.584A>G	p.His195Arg	missense_variant	Exon 5 of 7	1		ENSP00000437563.1	F5H6K3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250676

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000617

AC:

AN:

1458196

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725236

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000131

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.088

DEOGEN2

Benign

0.018

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.00099

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.89

L;L;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.58

N;N;N

REVEL

Benign

0.019

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.13

B;B;.

Vest4

0.10

MVP

0.030

MPC

0.26, 0.066

ClinPred

0.013

GERP RS

-2.8

Varity_R

0.043

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: 1

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over