Genetic Variant KLRC2:p.Ser216Thr (chr12-10431167-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002260.4(KLRC2):c.646T>A(p.Ser216Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,548,764 control chromosomes in the GnomAD database, including 20 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 (★).

Frequency

Genomes: 𝑓 0.000077 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00011 ( 20 hom. )

Consequence

KLRC2
NM_002260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12564558).

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC2	NM_002260.4 link	c.646T>A	p.Ser216Thr	missense_variant	Exon 6 of 6	ENST00000381902.7	NP_002251.2	P26717

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLRC2	ENST00000381902.7 link	c.646T>A	p.Ser216Thr	missense_variant	Exon 6 of 6	1	NM_002260.4	ENSP00000371327.2		P26717
ENSG00000255641	ENST00000539033.1 link	c.331+3319T>A		intron_variant	Intron 3 of 6	1		ENSP00000437563.1		F5H6K3

Frequencies

GnomAD3 genomes

AF:

0.0000774

AC:

AN:

142202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000537

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000691

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:

0.000123

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000998

AC:

AN:

240392

Hom.:

AF XY:

0.0000998

AC XY:

AN XY:

130202

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:

0.00

Gnomad FIN exome

AF:

0.000144

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000510

GnomAD4 exome

AF:

0.000106

AC:

149

AN:

1406562

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

700412

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000973

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.0000774

AC:

AN:

142202

Hom.:

Cov.:

AF XY:

0.0000723

AC XY:

AN XY:

69202

show subpopulations

Gnomad4 AFR

AF:

0.0000537

Gnomad4 AMR

AF:

0.0000691

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000123

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000276

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000100

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646T>A (p.S216T) alteration is located in exon 6 (coding exon 6) of the KLRC2 gene. This alteration results from a T to A substitution at nucleotide position 646, causing the serine (S) at amino acid position 216 to be replaced by a threonine (T). 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

0.20

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.85

DANN

Benign

0.84

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.47

.;T;T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.83

PROVEAN

Benign

-1.8

N;.;N;N

REVEL

Benign

0.074

Sift

Benign

0.047

D;.;D;D

Sift4G

Benign

0.20

T;D;T;D

Vest4

0.040

MVP

0.30

MPC

0.32

ClinPred

0.089

GERP RS

-2.6

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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