NM_002261.3:c.55T>C

Variant names:

• chr12-10420496-A-G
• rs2682490
• NM_002261.3:c.55T>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.55T>C​(p.Trp19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.986 in 148,510 control chromosomes in the GnomAD database, including 72,217 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. W19S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.99 (72217 hom., cov: 21)
  • Exomes 𝑓: 1.0 (728263 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLRC3 NM_002261.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.431
• Publications: 19 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=7.8799366E-7).
• BP6: Variant 12-10420496-A-G is Benign according to our data. Variant chr12-10420496-A-G is described in ClinVar as Benign. ClinVar VariationId is 768516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.55T>C	p.Trp19Arg	missense	Exon 1 of 7	NP_002252.2	Q07444-1
	KLRC3	NM_007333.2		c.55T>C	p.Trp19Arg	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.55T>C	p.Trp19Arg	missense	Exon 1 of 7	ENSP00000379716.3	Q07444-1
	KLRC3	ENST00000381903.2	TSL:1	c.55T>C	p.Trp19Arg	missense	Exon 1 of 6	ENSP00000371328.2	Q07444-2
	ENSG00000255641	ENST00000539033.1	TSL:1	c.332-1998T>C		intron	N/A	ENSP00000437563.1	F5H6K3

Frequencies

GnomAD3 genomes AF: 0.986 AC: 146302 AN: 148390 Hom.: 72159 Cov.: 21

Gnomad AFR AF: 0.950

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.998 AC: 248327 AN: 248926 AF XY: 0.998

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.999 AC: 1457834 AN: 1459264 Hom.: 728263 Cov.: 40 AF XY: 0.999 AC XY: 725431 AN XY: 726032

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.965 AC: 31006 AN: 32128

American (AMR) AF: 0.998 AC: 44598 AN: 44690

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26104 AN: 26104

East Asian (EAS) AF: 1.00 AC: 39638 AN: 39640

South Asian (SAS) AF: 1.00 AC: 86179 AN: 86192

European-Finnish (FIN) AF: 1.00 AC: 53378 AN: 53378

Middle Eastern (MID) AF: 0.998 AC: 5749 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1111055 AN: 1111112

Other (OTH) AF: 0.998 AC: 60127 AN: 60262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.986 AC: 146420 AN: 148510 Hom.: 72217 Cov.: 21 AF XY: 0.987 AC XY: 71280 AN XY: 72234

African (AFR) AF: 0.950 AC: 37950 AN: 39938

American (AMR) AF: 0.995 AC: 14690 AN: 14762

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3444 AN: 3444

East Asian (EAS) AF: 1.00 AC: 5034 AN: 5034

South Asian (SAS) AF: 1.00 AC: 4520 AN: 4520

European-Finnish (FIN) AF: 1.00 AC: 10136 AN: 10136

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67432 AN: 67442

Other (OTH) AF: 0.990 AC: 2022 AN: 2042

Alfa AF: 0.994 Hom.: 12159

ExAC AF: 0.995 AC: 120791

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	0.052
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.055
DANN	Benign	0.51
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	7.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N
PhyloP100		-0.43
PrimateAI	Benign	0.31	T
PROVEAN	Benign	6.4	N
REVEL	Benign	0.098
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.26		Gain of methylation at K18 (P = 0.0483)
MPC		0.37
ClinPred		0.0065	T
GERP RS		0.094
PromoterAI		0.058	Neutral
Varity_R		0.060
gMVP		0.039
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: rs2682490; hg19: chr12-10573095; COSMIC: COSV67249820;