12-10435821-C-T

Variant summary

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

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. 11/18 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

Scores

2
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0250
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]

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=0.077129304).
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLRC2NM_002260.4 linkc.166G>A p.Asp56Asn missense_variant Exon 1 of 6 ENST00000381902.7 NP_002251.2 P26717

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLRC2ENST00000381902.7 linkc.166G>A p.Asp56Asn missense_variant Exon 1 of 6 1 NM_002260.4 ENSP00000371327.2 P26717
ENSG00000255641ENST00000539033.1 linkc.166G>A p.Asp56Asn missense_variant Exon 1 of 7 1 ENSP00000437563.1 F5H6K3

Frequencies

GnomAD3 genomes
AF:
0.000190
AC:
27
AN:
142048
Hom.:
7
Cov.:
29
show subpopulations
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
GnomAD3 exomes
AF:
0.0000867
AC:
21
AN:
242154
Hom.:
4
AF XY:
0.0000840
AC XY:
11
AN XY:
130942
show subpopulations
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 SAS 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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 NFE exome
AF:
0.000291
Gnomad4 OTH exome
AF:
0.0000692
GnomAD4 genome
AF:
0.000190
AC:
27
AN:
142168
Hom.:
7
Cov.:
29
AF XY:
0.000202
AC XY:
14
AN XY:
69298
show subpopulations
Gnomad4 AFR
AF:
0.000161
Gnomad4 AMR
AF:
0.000137
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000293
Gnomad4 OTH
AF:
0.00
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

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.166G>A (p.D56N) alteration is located in exon 1 (coding exon 1) of the KLRC2 gene. This alteration results from a G to A substitution at nucleotide position 166, causing the aspartic acid (D) at amino acid position 56 to be replaced by an asparagine (N). 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
0.079
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;.;T
M_CAP
Benign
0.00083
T
MetaRNN
Benign
0.077
T;T;T
MetaSVM
Benign
-1.1
T
PROVEAN
Uncertain
-3.2
D;D;D
REVEL
Benign
0.014
Sift
Benign
0.13
T;T;T
Sift4G
Benign
0.072
T;T;T
Vest4
0.26
MVP
0.081
MPC
0.62
ClinPred
0.11
T
GERP RS
0.76
gMVP
0.079

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147031208; hg19: chr12-10588420; COSMIC: COSV67899986; COSMIC: COSV67899986; API