chr12-10409010-C-A

Variant names:

• chr12-10409010-C-A
• rs993640495
• NM_013431.2:c.188G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013431.2(KLRC4):​c.188G>T​(p.Gly63Val) variant causes a missense, splice region 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. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLRC4 NM_013431.2 missense, splice_region
• Scores: Splicing: ADA: 0.01771
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.87
• Publications: 0 publications found

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:48357): (KLRC4-KLRK1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring KLRC4 (killer cell lectin-like receptor subfamily C, member 4) and KLRK1 (killer cell lectin-like receptor subfamily K, member 1) genes on chromosome 12. The read-through transcript includes an alternate 5' exon and lacks a significant portion of the KLRC4 coding sequence, including the start codon, and it thus encodes the KLRK1 protein. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14363948).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013431.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC4	NM_013431.2	MANE Select	c.188G>T	p.Gly63Val	missense splice_region	Exon 2 of 4	NP_038459.1	O43908
	KLRC4-KLRK1	NM_001199805.1		c.-487G>T		splice_region	Exon 2 of 13	NP_001186734.1	P26718-1
	KLRC4-KLRK1	NM_001199805.1		c.-487G>T		5_prime_UTR	Exon 2 of 13	NP_001186734.1	P26718-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLRC4	ENST00000309384.3	TSL:1 MANE Select	c.188G>T	p.Gly63Val	missense splice_region	Exon 2 of 4	ENSP00000310216.1	O43908
	KLRC4-KLRK1	ENST00000539300.5	TSL:2	n.161G>T		splice_region non_coding_transcript_exon	Exon 2 of 13	ENSP00000455951.1	H3BQV0
	KLRC4	ENST00000718241.1		c.188G>T	p.Gly63Val	missense splice_region	Exon 2 of 4	ENSP00000520686.1	O43908

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.2
DANN	Benign	0.86
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		-1.9
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.051
Sift	Benign	0.13	T
Sift4G	Benign	0.067	T
Polyphen		1.0	D
Vest4		0.068
MutPred		0.49		Gain of catalytic residue at P66 (P = 8e-04)
MVP		0.44
MPC		0.38
ClinPred		0.33	T
GERP RS		-2.1
Varity_R		0.079
gMVP		0.14
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.018
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.50		Position offset: 0

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

Other links and lift over

dbSNP: rs993640495; hg19: chr12-10561609;