12-10409511-C-G

Position:

• chr12-10409511-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013431.2(KLRC4):​c.65G>C​(p.Arg22Thr) 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. 13/21 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)
• Consequence: KLRC4 NM_013431.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.15

Genes affected

KLRC4 (HGNC:6377): (killer cell lectin like receptor C4) 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. This gene is a member of the NKG2 group of genes that are expressed primarily in natural killer (NK) cells. These family members encode transmembrane proteins that are characterized by a type II membrane orientation (have an extracellular C-terminus) and the presence of a C-type lectin domain. This family member is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed in NK cells. Read-through transcription exists between this gene and the downstream KLRK1 (killer cell lectin-like receptor subfamily K, member 1) family member. [provided by RefSeq, Dec 2010]

KLRC4-KLRK1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18761387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC4	NM_013431.2	c.65G>C	p.Arg22Thr	missense_variant	1/4	ENST00000309384.3	NP_038459.1
KLRC4-KLRK1	NM_001199805.1	c.-487-501G>C		intron_variant			NP_001186734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC4	ENST00000309384.3	c.65G>C	p.Arg22Thr	missense_variant	1/4	1	NM_013431.2	ENSP00000310216	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Dec 01, 2022

The c.65G>C (p.R22T) alteration is located in exon 1 (coding exon 1) of the KLRC4 gene. This alteration results from a G to C substitution at nucleotide position 65, causing the arginine (R) at amino acid position 22 to be replaced by a threonine (T). 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	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.1
DANN	Benign	0.86
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.033
Sift	Benign	0.045	D
Sift4G	Benign	0.074	T
Polyphen		1.0	D
Vest4		0.11
MutPred		0.39		Gain of loop (P = 0.0166);
MVP		0.31
MPC		0.75
ClinPred		0.64	D
GERP RS		-3.5
Varity_R		0.081
gMVP		0.059

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: chr12-10562110;