12-10433894-C-T

Variant names:

• chr12-10433894-C-T
• rs769246569
• NM_002260.4:c.380G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002260.4(KLRC2):​c.380G>A​(p.Ser127Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,408,508 control chromosomes in the GnomAD database, including 1 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000043 (1 hom.)
• Consequence: KLRC2 NM_002260.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.799

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=0.13103458).
• BP6: Variant 12-10433894-C-T is Benign according to our data. Variant chr12-10433894-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2218081.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC2	NM_002260.4	c.380G>A	p.Ser127Asn	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.380G>A	p.Ser127Asn	missense_variant	Exon 4 of 6	1	NM_002260.4	ENSP00000371327.2
ENSG00000255641	ENST00000539033.1	c.331+592G>A		intron_variant	Intron 3 of 6	1		ENSP00000437563.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD3 exomes AF: 0.00000827 AC: 2 AN: 241942 Hom.: 0 AF XY: 0.00000764 AC XY: 1 AN XY: 130856

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000426 AC: 6 AN: 1408508 Hom.: 1 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000454

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: 0.00000373

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 26, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.41
DANN	Benign	0.71
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00098	N
LIST_S2	Benign	0.82	.;T;D;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	2.9	N;.;N;N
REVEL	Benign	0.019
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.14
MutPred		0.48		Gain of catalytic residue at S125 (P = 0.0013);.;Gain of catalytic residue at S125 (P = 0.0013);.;
MVP		0.12
MPC		0.30
ClinPred		0.043	T
GERP RS		-3.7
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs769246569; hg19: chr12-10586493;