rs2246809

Variant names:

• chr12-10404445-A-G
• rs2246809
• ENST00000539300.5:n.*17+3191T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000539300.5(KLRC4-KLRK1):​n.*17+3191T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 151,980 control chromosomes in the GnomAD database, including 48,256 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48256 hom., cov: 32)
• Consequence: KLRC4-KLRK1 ENST00000539300.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.52
• Publications: 15 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC4-KLRK1	NM_001199805.1	c.-181+3191T>C		intron_variant	Intron 4 of 12		NP_001186734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLRC4-KLRK1	ENST00000539300.5	n.*17+3191T>C		intron_variant	Intron 4 of 12	2		ENSP00000455951.1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120879 AN: 151860 Hom.: 48213 Cov.: 32

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.885

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.824

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.785

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.796 AC: 120983 AN: 151980 Hom.: 48256 Cov.: 32 AF XY: 0.798 AC XY: 59265 AN XY: 74278

African (AFR) AF: 0.743 AC: 30835 AN: 41488

American (AMR) AF: 0.853 AC: 13030 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2786 AN: 3470

East Asian (EAS) AF: 0.768 AC: 3966 AN: 5164

South Asian (SAS) AF: 0.884 AC: 4263 AN: 4822

European-Finnish (FIN) AF: 0.810 AC: 8588 AN: 10596

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.810 AC: 54931 AN: 67856

Other (OTH) AF: 0.787 AC: 1663 AN: 2112

Alfa AF: 0.798 Hom.: 7330

Bravo AF: 0.793

Asia WGS AF: 0.836 AC: 2894 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.40
DANN	Benign	0.36
PhyloP100		-2.5

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

Other links and lift over

dbSNP: rs2246809; hg19: chr12-10557044;