12-10415727-G-T

Position:

• chr12-10415727-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002261.3(KLRC3):​c.655C>A​(p.Gln219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLRC3 NM_002261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.27

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05636823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC3	NM_002261.3	c.655C>A	p.Gln219Lys	missense_variant	6/7	ENST00000396439.7	NP_002252.2
KLRC3	NM_007333.2	c.655C>A	p.Gln219Lys	missense_variant	6/6		NP_031359.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC3	ENST00000396439.7	c.655C>A	p.Gln219Lys	missense_variant	6/7	5	NM_002261.3	ENSP00000379716	A2
KLRC3	ENST00000381903.2	c.655C>A	p.Gln219Lys	missense_variant	6/6	1		ENSP00000371328	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461332 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The c.655C>A (p.Q219K) alteration is located in exon 6 (coding exon 6) of the KLRC3 gene. This alteration results from a C to A substitution at nucleotide position 655, causing the glutamine (Q) at amino acid position 219 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.011
DANN	Benign	0.33
DEOGEN2	Benign	0.017	T;.;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.097	T;T;T
M_CAP	Benign	0.00080	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.88	T;T;T
Sift4G	Benign	0.85	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.10
MutPred		0.47		Gain of catalytic residue at Q219 (P = 0);Gain of catalytic residue at Q219 (P = 0);Gain of catalytic residue at Q219 (P = 0);
MVP		0.030
MPC		0.27, 0.069
ClinPred		0.053	T
GERP RS		-5.0
Varity_R		0.078
gMVP		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-10568326;