12-10418495-C-A

Position:

• chr12-10418495-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002261.3(KLRC3):​c.335G>T​(p.Arg112Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,574,494 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (13 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (15 hom.)
• Consequence: KLRC3 NM_002261.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.68

Genes affected

KLRC3 (HGNC:6376): (killer cell lectin like receptor C3) 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. KLRC3 is a member of the NKG2 group which 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 NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004924208).
• BP6: Variant 12-10418495-C-A is Benign according to our data. Variant chr12-10418495-C-A is described in ClinVar as [Benign]. Clinvar id is 786221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00765 (1164/152236) while in subpopulation AFR AF= 0.0269 (1117/41546). AF 95% confidence interval is 0.0256. There are 13 homozygotes in gnomad4. There are 534 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC3	NM_002261.3	c.335G>T	p.Arg112Leu	missense_variant	4/7	ENST00000396439.7	NP_002252.2
KLRC3	NM_007333.2	c.335G>T	p.Arg112Leu	missense_variant	4/6		NP_031359.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC3	ENST00000396439.7	c.335G>T	p.Arg112Leu	missense_variant	4/7	5	NM_002261.3	ENSP00000379716	A2
KLRC3	ENST00000381903.2	c.335G>T	p.Arg112Leu	missense_variant	4/6	1		ENSP00000371328	P2

Frequencies

GnomAD3 genomes AF: 0.00763 AC: 1160 AN: 152118 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00219 AC: 517 AN: 235728 Hom.: 8 AF XY: 0.00161 AC XY: 205 AN XY: 127380

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00131

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: 0.0000641

Gnomad OTH exome AF: 0.00141

GnomAD4 exome AF: 0.000828 AC: 1177 AN: 1422258 Hom.: 15 Cov.: 32 AF XY: 0.000709 AC XY: 503 AN XY: 709046

Gnomad4 AFR exome AF: 0.0295

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000480

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000388

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00765 AC: 1164 AN: 152236 Hom.: 13 Cov.: 34 AF XY: 0.00717 AC XY: 534 AN XY: 74432

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00360 Hom.: 2

Bravo AF: 0.00879

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00267 AC: 324

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 11, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0050
DANN	Benign	0.19
DEOGEN2	Benign	0.0044	T;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.15	T;T;T
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.60	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.12
MVP		0.16
MPC		0.27, 0.067
ClinPred		0.00084	T
GERP RS		-4.8
Varity_R		0.042
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150804808; hg19: chr12-10571094;