12-10435967-G-A

Variant names:

• chr12-10435967-G-A
• rs149277235
• NM_002260.4:c.20C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002260.4(KLRC2):​c.20C>T​(p.Thr7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,605,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: KLRC2 NM_002260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.27

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013810486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC2	NM_002260.4	c.20C>T	p.Thr7Ile	missense_variant	Exon 1 of 6	ENST00000381902.7	NP_002251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLRC2	ENST00000381902.7	c.20C>T	p.Thr7Ile	missense_variant	Exon 1 of 6	1	NM_002260.4	ENSP00000371327.2
ENSG00000255641	ENST00000539033.1	c.20C>T	p.Thr7Ile	missense_variant	Exon 1 of 7	1		ENSP00000437563.1

Frequencies

GnomAD3 genomes AF: 0.000155 AC: 23 AN: 148516 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000328

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000408 AC: 102 AN: 250192 Hom.: 0 AF XY: 0.000451 AC XY: 61 AN XY: 135242

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000778

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000415 AC: 604 AN: 1456536 Hom.: 0 Cov.: 138 AF XY: 0.000397 AC XY: 288 AN XY: 724652

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000518

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.000155 AC: 23 AN: 148642 Hom.: 0 Cov.: 32 AF XY: 0.000179 AC XY: 13 AN XY: 72634

Gnomad4 AFR AF: 0.0000250

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000328

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000506 Hom.: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000873 AC: 106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20C>T (p.T7I) alteration is located in exon 1 (coding exon 1) of the KLRC2 gene. This alteration results from a C to T substitution at nucleotide position 20, causing the threonine (T) at amino acid position 7 to be replaced by an isoleucine (I). 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	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.053
DANN	Benign	0.58
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.53	T;.;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.91	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.31	T;T;T
Vest4		0.11
MVP		0.030
MPC		0.58
ClinPred		0.017	T
GERP RS		-2.2
gMVP		0.082

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

Publications

LitVar

Other links and lift over

dbSNP: rs149277235; hg19: chr12-10588566; COSMIC: COSV67899401; COSMIC: COSV67899401;