chr12-10435821-C-T

Variant names:

• chr12-10435821-C-T
• rs147031208
• NM_002260.4:c.166G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002260.4(KLRC2):​c.166G>A​(p.Asp56Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,548,904 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D56D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (7 hom., cov: 29)
  • Exomes 𝑓: 0.00022 (54 hom.)
• Consequence: KLRC2 NM_002260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0250
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077129304).
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002260.4. 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
	KLRC2	NM_002260.4	MANE Select	c.166G>A	p.Asp56Asn	missense	Exon 1 of 6	NP_002251.2	P26717

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC2	ENST00000381902.7	TSL:1 MANE Select	c.166G>A	p.Asp56Asn	missense	Exon 1 of 6	ENSP00000371327.2	P26717
	ENSG00000255641	ENST00000539033.1	TSL:1	c.166G>A	p.Asp56Asn	missense	Exon 1 of 7	ENSP00000437563.1	F5H6K3
	KLRC2	ENST00000381901.5	TSL:5	c.166G>A	p.Asp56Asn	missense	Exon 1 of 6	ENSP00000371326.1	J3KPJ4

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 27 AN: 142048 Hom.: 7 Cov.: 29

Gnomad AFR AF: 0.000161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

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: 0.000293

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000867 AC: 21 AN: 242154 AF XY: 0.0000840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000225 AC: 316 AN: 1406736 Hom.: 54 Cov.: 30 AF XY: 0.000194 AC XY: 136 AN XY: 700302

African (AFR) AF: 0.00 AC: 0 AN: 31158

American (AMR) AF: 0.0000227 AC: 1 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24960

East Asian (EAS) AF: 0.00 AC: 0 AN: 37438

South Asian (SAS) AF: 0.00 AC: 0 AN: 84410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.000291 AC: 311 AN: 1070070

Other (OTH) AF: 0.0000692 AC: 4 AN: 57818

GnomAD4 genome AF: 0.000190 AC: 27 AN: 142168 Hom.: 7 Cov.: 29 AF XY: 0.000202 AC XY: 14 AN XY: 69298

African (AFR) AF: 0.000161 AC: 6 AN: 37306

American (AMR) AF: 0.000137 AC: 2 AN: 14546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3298

East Asian (EAS) AF: 0.00 AC: 0 AN: 4758

South Asian (SAS) AF: 0.00 AC: 0 AN: 4566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000293 AC: 19 AN: 64746

Other (OTH) AF: 0.00 AC: 0 AN: 1956

Alfa AF: 0.000126 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000356 AC: 3

ExAC AF: 0.000101 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.00083	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.025
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.014
Sift	Benign	0.13	T
Sift4G	Benign	0.072	T
Vest4		0.26
MVP		0.081
MPC		0.62
ClinPred		0.11	T
GERP RS		0.76
PromoterAI		-0.030	Neutral
gMVP		0.079
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147031208; hg19: chr12-10588420; COSMIC: COSV67899986; COSMIC: COSV67899986;