12-10420495-C-G

Variant names:

• chr12-10420495-C-G
• rs2682491
• NM_002261.3:c.56G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002261.3(KLRC3):​c.56G>C​(p.Trp19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 145,218 control chromosomes in the GnomAD database, including 22,714 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W19R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.54 (22714 hom., cov: 22)
  • Exomes 𝑓: 0.52 (117378 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLRC3 NM_002261.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.584
• Publications: 15 publications found

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]

ENSG00000255641 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.698558E-6).
• BP6: Variant 12-10420495-C-G is Benign according to our data. Variant chr12-10420495-C-G is described in ClinVar as Benign. ClinVar VariationId is 769385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002261.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC3	NM_002261.3	MANE Select	c.56G>C	p.Trp19Ser	missense	Exon 1 of 7	NP_002252.2	Q07444-1
	KLRC3	NM_007333.2		c.56G>C	p.Trp19Ser	missense	Exon 1 of 6	NP_031359.2	Q07444-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC3	ENST00000396439.7	TSL:5 MANE Select	c.56G>C	p.Trp19Ser	missense	Exon 1 of 7	ENSP00000379716.3	Q07444-1
	KLRC3	ENST00000381903.2	TSL:1	c.56G>C	p.Trp19Ser	missense	Exon 1 of 6	ENSP00000371328.2	Q07444-2
	ENSG00000255641	ENST00000539033.1	TSL:1	c.332-1997G>C		intron	N/A	ENSP00000437563.1	F5H6K3

Frequencies

GnomAD3 genomes AF: 0.537 AC: 77957 AN: 145102 Hom.: 22706 Cov.: 22

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.552

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.557

GnomAD2 exomes AF: 0.572 AC: 137566 AN: 240646 AF XY: 0.574

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.617

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.518 AC: 745254 AN: 1439754 Hom.: 117378 Cov.: 40 AF XY: 0.523 AC XY: 374962 AN XY: 716576

African (AFR) AF: 0.238 AC: 7850 AN: 32960

American (AMR) AF: 0.595 AC: 26274 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14463 AN: 25956

East Asian (EAS) AF: 0.553 AC: 21742 AN: 39312

South Asian (SAS) AF: 0.511 AC: 43699 AN: 85488

European-Finnish (FIN) AF: 0.598 AC: 30891 AN: 51672

Middle Eastern (MID) AF: 0.531 AC: 2985 AN: 5624

European-Non Finnish (NFE) AF: 0.517 AC: 566396 AN: 1094972

Other (OTH) AF: 0.519 AC: 30954 AN: 59616

GnomAD4 genome AF: 0.537 AC: 77988 AN: 145218 Hom.: 22714 Cov.: 22 AF XY: 0.535 AC XY: 37749 AN XY: 70512

African (AFR) AF: 0.271 AC: 10785 AN: 39854

American (AMR) AF: 0.624 AC: 9042 AN: 14502

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 1966 AN: 3368

East Asian (EAS) AF: 0.556 AC: 2755 AN: 4954

South Asian (SAS) AF: 0.532 AC: 2375 AN: 4466

European-Finnish (FIN) AF: 0.635 AC: 6238 AN: 9828

Middle Eastern (MID) AF: 0.556 AC: 160 AN: 288

European-Non Finnish (NFE) AF: 0.661 AC: 43011 AN: 65096

Other (OTH) AF: 0.560 AC: 1120 AN: 2000

Alfa AF: 0.533 Hom.: 2758

ExAC AF: 0.551 AC: 66872

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.62
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000087	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.58
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.019	D
Polyphen		0.0	B
Vest4		0.049
MPC		0.34
ClinPred		0.024	T
GERP RS		-0.20
PromoterAI		0.026	Neutral
Varity_R		0.075
gMVP		0.085
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2682491; hg19: chr12-10573094; COSMIC: COSV67249876;