chr12-10420496-A-G

Position:

• chr12-10420496-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W19P) has been classified as Likely 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC3	NM_002261.3	c.55T>C	p.Trp19Arg	missense_variant	1/7	ENST00000396439.7	NP_002252.2
KLRC3	NM_007333.2	c.55T>C	p.Trp19Arg	missense_variant	1/6		NP_031359.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC3	ENST00000396439.7	c.55T>C	p.Trp19Arg	missense_variant	1/7	5	NM_002261.3	ENSP00000379716.3
KLRC3	ENST00000381903.2	c.55T>C	p.Trp19Arg	missense_variant	1/6	1		ENSP00000371328.2
ENSG00000255641	ENST00000539033.1	c.332-1998T>C		intron_variant		1		ENSP00000437563.1

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

GnomAD3 exomes AF: 0.998 AC: 248327 AN: 248926 Hom.: 123890 AF XY: 0.998 AC XY: 134535 AN XY: 134764

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 SAS 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

Gnomad4 AFR exome AF: 0.965

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

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

Gnomad4 AFR AF: 0.950

Gnomad4 AMR AF: 0.995

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.990

Alfa AF: 0.994 Hom.: 12159

ExAC AF: 0.995 AC: 120791

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	Jul 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	7.9e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	6.4	N;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.015
MutPred		0.26		Gain of methylation at K18 (P = 0.0483);Gain of methylation at K18 (P = 0.0483);
MPC		0.37
ClinPred		0.0065	T
GERP RS		0.094
Varity_R		0.060
gMVP		0.039

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: rs2682490; hg19: chr12-10573095; COSMIC: COSV67249820;