chr12-10435375-C-A

Position:

• chr12-10435375-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000381902.7(KLRC2):​c.223G>T​(p.Val75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLRC2 ENST00000381902.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.564

Genes affected

KLRC2 (HGNC:6375): (killer cell lectin like receptor C2) 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. The group, designated KLRC (NKG2) 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 KLRC (NKG2) gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. KLRC2 alternative splice variants have been described but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34810716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC2	NM_002260.4	c.223G>T	p.Val75Phe	missense_variant	2/6	ENST00000381902.7	NP_002251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC2	ENST00000381902.7	c.223G>T	p.Val75Phe	missense_variant	2/6	1	NM_002260.4	ENSP00000371327	P4
KLRC2	ENST00000381901.5	c.223G>T	p.Val75Phe	missense_variant	2/6	5		ENSP00000371326	A1
KLRC2	ENST00000536833.6	c.46G>T	p.Val16Phe	missense_variant	3/7	5		ENSP00000444754	A2
KLRC2	ENST00000535069.5	c.142G>T	p.Val48Phe	missense_variant, NMD_transcript_variant	2/7	5		ENSP00000438983

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461432 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jan 24, 2024

The c.223G>T (p.V75F) alteration is located in exon 2 (coding exon 2) of the KLRC2 gene. This alteration results from a G to T substitution at nucleotide position 223, causing the valine (V) at amino acid position 75 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.9
DANN	Uncertain	0.99
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.016	N
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N;N
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.041
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Vest4		0.37
MutPred		0.43		Gain of catalytic residue at V75 (P = 0.0065);Gain of catalytic residue at V75 (P = 0.0065);Gain of catalytic residue at V75 (P = 0.0065);.;
MVP		0.17
MPC		2.4
ClinPred		0.55	D
GERP RS		0.65
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-10587974;