12-10372766-G-C

Position:

• chr12-10372766-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007360.4(KLRK1):​c.*348C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 263,650 control chromosomes in the GnomAD database, including 52,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27506 hom., cov: 32)
  • Exomes 𝑓: 0.66 (24611 hom.)
• Consequence: KLRK1 NM_007360.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.404

Genes affected

KLRK1 (HGNC:18788): (killer cell lectin like receptor K1) 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 NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed in NK cells. This gene encodes a member of the NKG2 family. The encoded transmembrane protein is characterized by a type II membrane orientation (has an extracellular C terminus) and the presence of a C-type lectin domain. It binds to a diverse family of ligands that include MHC class I chain-related A and B proteins and UL-16 binding proteins, where ligand-receptor interactions can result in the activation of NK and T cells. The surface expression of these ligands is important for the recognition of stressed cells by the immune system, and thus this protein and its ligands are therapeutic targets for the treatment of immune diseases and cancers. Read-through transcription exists between this gene and the upstream KLRC4 (killer cell lectin-like receptor subfamily C, member 4) family member in the same cluster. [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]

KLRK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-10372766-G-C is Benign according to our data. Variant chr12-10372766-G-C is described in ClinVar as [Benign]. Clinvar id is 1238157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRK1	NM_007360.4	c.*348C>G		3_prime_UTR_variant	8/8	ENST00000240618.11	NP_031386.2
KLRC4-KLRK1	NM_001199805.1	c.*348C>G		3_prime_UTR_variant	13/13		NP_001186734.1
KLRK1-AS1	NR_120430.1	n.266-1269G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRK1	ENST00000240618	c.*348C>G		3_prime_UTR_variant	8/8	1	NM_007360.4	ENSP00000240618.6

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87525 AN: 151962 Hom.: 27495 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.658 AC: 73420 AN: 111570 Hom.: 24611 Cov.: 0 AF XY: 0.646 AC XY: 39586 AN XY: 61326

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.645

Gnomad4 ASJ exome AF: 0.602

Gnomad4 EAS exome AF: 0.585

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.671

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.647

GnomAD4 genome AF: 0.576 AC: 87560 AN: 152080 Hom.: 27506 Cov.: 32 AF XY: 0.575 AC XY: 42713 AN XY: 74344

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.659

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.568

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.603

Alfa AF: 0.534 Hom.: 1843

Bravo AF: 0.562

Asia WGS AF: 0.543 AC: 1890 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 27995954) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.45

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

LitVar

Other links and lift over

dbSNP: rs1049174; hg19: chr12-10525365;