12-10420546-C-T

Position:

• chr12-10420546-C-T

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.5G>A​(p.Ser2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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.

• Frequency:
  • Genomes: 𝑓 0.95 (58154 hom., cov: 19)
  • Exomes 𝑓: 0.71 (291638 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLRC3 NM_002261.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.196

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=4.398491E-5).
• BP6: Variant 12-10420546-C-T is Benign according to our data. Variant chr12-10420546-C-T is described in ClinVar as [Benign]. Clinvar id is 768517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC3	NM_002261.3	c.5G>A	p.Ser2Asn	missense_variant	1/7	ENST00000396439.7	NP_002252.2
KLRC3	NM_007333.2	c.5G>A	p.Ser2Asn	missense_variant	1/6		NP_031359.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC3	ENST00000396439.7	c.5G>A	p.Ser2Asn	missense_variant	1/7	5	NM_002261.3	ENSP00000379716.3
KLRC3	ENST00000381903.2	c.5G>A	p.Ser2Asn	missense_variant	1/6	1		ENSP00000371328.2
ENSG00000255641	ENST00000539033.1	c.332-2048G>A		intron_variant		1		ENSP00000437563.1

Frequencies

GnomAD3 genomes AF: 0.954 AC: 122030 AN: 127978 Hom.: 58095 Cov.: 19

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.975

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.990

Gnomad NFE AF: 0.956

Gnomad OTH AF: 0.950

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.709 AC: 987155 AN: 1391388 Hom.: 291638 Cov.: 45 AF XY: 0.722 AC XY: 498093 AN XY: 689542

Gnomad4 AFR exome AF: 0.852

Gnomad4 AMR exome AF: 0.881

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 0.907

Gnomad4 SAS exome AF: 0.873

Gnomad4 FIN exome AF: 0.826

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.774

GnomAD4 genome AF: 0.954 AC: 122150 AN: 128100 Hom.: 58154 Cov.: 19 AF XY: 0.951 AC XY: 58455 AN XY: 61456

Gnomad4 AFR AF: 0.936

Gnomad4 AMR AF: 0.967

Gnomad4 ASJ AF: 0.969

Gnomad4 EAS AF: 0.974

Gnomad4 SAS AF: 0.978

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.956

Gnomad4 OTH AF: 0.950

Alfa AF: 0.892 Hom.: 9938

ExAC AF: 0.577 AC: 69850

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	0.050
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.15
DANN	Benign	0.60
DEOGEN2	Benign	0.0030	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.000044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.96	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	2.6	N;N
REVEL	Benign	0.012
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.031
MPC		0.20
ClinPred		0.0034	T
GERP RS		-1.0
Varity_R		0.036
gMVP		0.024

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: rs2682489; hg19: chr12-10573145; COSMIC: COSV67249828;