chr12-10433939-C-T

Variant names:

• chr12-10433939-C-T
• rs762754548
• NM_002260.4:c.335G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002260.4(KLRC2):​c.335G>A​(p.Arg112His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,544,840 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000035 (1 hom., cov: 27)
  • Exomes 𝑓: 0.000078 (14 hom.)
• Consequence: KLRC2 NM_002260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.46

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]

ENSG00000255641 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058796436).
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC2	NM_002260.4	c.335G>A	p.Arg112His	missense_variant	Exon 4 of 6	ENST00000381902.7	NP_002251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLRC2	ENST00000381902.7	c.335G>A	p.Arg112His	missense_variant	Exon 4 of 6	1	NM_002260.4	ENSP00000371327.2
ENSG00000255641	ENST00000539033.1	c.331+547G>A		intron_variant	Intron 3 of 6	1		ENSP00000437563.1

Frequencies

GnomAD3 genomes AF: 0.0000352 AC: 5 AN: 141882 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.0000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000689

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: 0.0000463

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000361 AC: 8 AN: 221450 Hom.: 0 AF XY: 0.0000501 AC XY: 6 AN XY: 119748

Gnomad AFR exome AF: 0.0000696

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000777 AC: 109 AN: 1402958 Hom.: 14 Cov.: 30 AF XY: 0.0000745 AC XY: 52 AN XY: 698304

Gnomad4 AFR exome AF: 0.0000325

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.000180

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000823

Gnomad4 OTH exome AF: 0.0000521

GnomAD4 genome AF: 0.0000352 AC: 5 AN: 141882 Hom.: 1 Cov.: 27 AF XY: 0.0000434 AC XY: 3 AN XY: 69066

Gnomad4 AFR AF: 0.0000269

Gnomad4 AMR AF: 0.0000689

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000463

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000339 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335G>A (p.R112H) alteration is located in exon 4 (coding exon 4) of the KLRC2 gene. This alteration results from a G to A substitution at nucleotide position 335, causing the arginine (R) at amino acid position 112 to be replaced by a histidine (H). 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	Benign	0.068
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.045
DANN	Benign	0.38
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00072	N
LIST_S2	Benign	0.40	.;T;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	1.9	N;.;N;N
REVEL	Benign	0.0050
Sift	Benign	0.50	T;.;T;T
Sift4G	Benign	0.47	T;T;T;T
Vest4		0.25
MutPred		0.45		Gain of catalytic residue at H116 (P = 0);.;Gain of catalytic residue at H116 (P = 0);.;
MVP		0.067
MPC		0.39
ClinPred		0.024	T
GERP RS		-1.7
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs762754548; hg19: chr12-10586538;