12-10434512-A-G

Position:

• chr12-10434512-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000381902.7(KLRC2):​c.305T>C​(p.Phe102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 1,553,216 control chromosomes in the GnomAD database, including 546,972 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.80 (44790 hom., cov: 45)
  • Exomes 𝑓: 0.86 (502182 hom.)
• Consequence: KLRC2 ENST00000381902.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.252

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.8393117E-6).
• BP6: Variant 12-10434512-A-G is Benign according to our data. Variant chr12-10434512-A-G is described in ClinVar as [Benign]. Clinvar id is 768518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC2	NM_002260.4	c.305T>C	p.Phe102Ser	missense_variant	3/6	ENST00000381902.7	NP_002251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC2	ENST00000381902.7	c.305T>C	p.Phe102Ser	missense_variant	3/6	1	NM_002260.4	ENSP00000371327	P4
KLRC2	ENST00000536833.6	c.128T>C	p.Phe43Ser	missense_variant	4/7	5		ENSP00000444754	A2
KLRC2	ENST00000381901.5	c.331+483T>C		intron_variant		5		ENSP00000371326	A1
KLRC2	ENST00000535069.5	c.224T>C	p.Phe75Ser	missense_variant, NMD_transcript_variant	3/7	5		ENSP00000438983

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120383 AN: 151312 Hom.: 44780 Cov.: 45

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.787

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.809

GnomAD3 exomes AF: 0.821 AC: 204189 AN: 248608 Hom.: 79906 AF XY: 0.823 AC XY: 110650 AN XY: 134422

Gnomad AFR exome AF: 0.641

Gnomad AMR exome AF: 0.774

Gnomad ASJ exome AF: 0.823

Gnomad EAS exome AF: 0.808

Gnomad SAS exome AF: 0.739

Gnomad FIN exome AF: 0.853

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.858 AC: 1202933 AN: 1401790 Hom.: 502182 Cov.: 35 AF XY: 0.855 AC XY: 597604 AN XY: 698790

Gnomad4 AFR exome AF: 0.633

Gnomad4 AMR exome AF: 0.783

Gnomad4 ASJ exome AF: 0.823

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.741

Gnomad4 FIN exome AF: 0.861

Gnomad4 NFE exome AF: 0.880

Gnomad4 OTH exome AF: 0.836

GnomAD4 genome AF: 0.795 AC: 120450 AN: 151426 Hom.: 44790 Cov.: 45 AF XY: 0.793 AC XY: 58743 AN XY: 74046

Gnomad4 AFR AF: 0.643

Gnomad4 AMR AF: 0.810

Gnomad4 ASJ AF: 0.816

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.726

Gnomad4 FIN AF: 0.847

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.810

Alfa AF: 0.841 Hom.: 4605

ExAC AF: 0.818 AC: 99261

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.6
DANN	Benign	0.12
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00013	N
LIST_S2	Benign	0.064	T;.;T
MetaRNN	Benign	0.0000048	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	3.6	N;N;N
REVEL	Benign	0.016
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.034
MPC		0.094
ClinPred		0.011	T
GERP RS		-3.7
gMVP		0.16

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: rs1141715; hg19: chr12-10587111; COSMIC: COSV67899331; COSMIC: COSV67899331;