12-10379727-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007360.4(KLRK1):c.214A>G(p.Thr72Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,610,626 control chromosomes in the GnomAD database, including 520,524 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (43298 hom., cov: 31)
  • Exomes 𝑓: 0.81 (477226 hom.)
• Consequence: KLRK1 NM_007360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

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:):

KLRK1-AS1 (HGNC:54868): (KLRK1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0851428E-6).
• 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/exons	MANE	UniProt
KLRK1	NM_007360.4	c.214A>G	p.Thr72Ala	missense_variant	4/8	ENST00000240618.11
KLRC4-KLRK1	NM_001199805.1	c.214A>G	p.Thr72Ala	missense_variant	9/13
KLRK1-AS1	NR_120430.1	n.393T>C		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLRK1	ENST00000240618.11	c.214A>G	p.Thr72Ala	missense_variant	4/8	1	NM_007360.4	P1
KLRK1-AS1	ENST00000500682.1	n.393T>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113519 AN: 151912 Hom.: 43277 Cov.: 31

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.884

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.760

GnomAD3 exomes AF: 0.808 AC: 201579 AN: 249454 Hom.: 82203 AF XY: 0.812 AC XY: 109435 AN XY: 134778

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.788

Gnomad EAS exome AF: 0.759

Gnomad SAS exome AF: 0.886

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.801

GnomAD4 exome AF: 0.807 AC: 1177745 AN: 1458596 Hom.: 477226 Cov.: 45 AF XY: 0.810 AC XY: 587957 AN XY: 725450

Gnomad4 AFR exome AF: 0.570

Gnomad4 AMR exome AF: 0.882

Gnomad4 ASJ exome AF: 0.789

Gnomad4 EAS exome AF: 0.789

Gnomad4 SAS exome AF: 0.880

Gnomad4 FIN exome AF: 0.809

Gnomad4 NFE exome AF: 0.808

Gnomad4 OTH exome AF: 0.787

GnomAD4 genome AF: 0.747 AC: 113585 AN: 152030 Hom.: 43298 Cov.: 31 AF XY: 0.749 AC XY: 55700 AN XY: 74324

Gnomad4 AFR AF: 0.577

Gnomad4 AMR AF: 0.828

Gnomad4 ASJ AF: 0.796

Gnomad4 EAS AF: 0.774

Gnomad4 SAS AF: 0.884

Gnomad4 FIN AF: 0.810

Gnomad4 NFE AF: 0.808

Gnomad4 OTH AF: 0.763

Alfa AF: 0.795 Hom.: 125241

Bravo AF: 0.738

TwinsUK AF: 0.807 AC: 2994

ALSPAC AF: 0.799 AC: 3080

ESP6500AA AF: 0.579 AC: 2552

ESP6500EA AF: 0.800 AC: 6877

ExAC AF: 0.803 AC: 97496

Asia WGS AF: 0.816 AC: 2836 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.3
Dann	Benign	0.91
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0069	N
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.010
Sift	Benign	0.96	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.044
MPC		0.18
ClinPred		0.00087	T
GERP RS		-1.4
gMVP		0.14

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: rs2255336; hg19: chr12-10532326; COSMIC: COSV53698409; COSMIC: COSV53698409;