12-10420495-C-G

Position:

• chr12-10420495-C-G

Variant summary

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

The ENST00000539033.1(ENSG00000255641):​c.332-1997G>C variant causes a intron 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22714 hom., cov: 22)
  • Exomes 𝑓: 0.52 (117378 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000255641 ENST00000539033.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.584

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=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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC3	NM_002261.3	c.56G>C	p.Trp19Ser	missense_variant	1/7	ENST00000396439.7	NP_002252.2
KLRC3	NM_007333.2	c.56G>C	p.Trp19Ser	missense_variant	1/6		NP_031359.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC3	ENST00000396439.7	c.56G>C	p.Trp19Ser	missense_variant	1/7	5	NM_002261.3	ENSP00000379716.3
KLRC3	ENST00000381903.2	c.56G>C	p.Trp19Ser	missense_variant	1/6	1		ENSP00000371328.2
ENSG00000255641	ENST00000539033.1	c.332-1997G>C		intron_variant		1		ENSP00000437563.1

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

GnomAD3 exomes AF: 0.572 AC: 137566 AN: 240646 Hom.: 37605 AF XY: 0.574 AC XY: 74722 AN XY: 130154

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 SAS exome AF: 0.537

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

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.595

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.553

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.519

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

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.584

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.532

Gnomad4 FIN AF: 0.635

Gnomad4 NFE AF: 0.661

Gnomad4 OTH AF: 0.560

Alfa AF: 0.533 Hom.: 2758

ExAC AF: 0.551 AC: 66872

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	0.12
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;T
MetaRNN	Benign	0.0000087	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.1	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.0	B;B
Vest4		0.049
MPC		0.34
ClinPred		0.024	T
GERP RS		-0.20
Varity_R		0.075
gMVP		0.085

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