rs2617170

Variant names:

• chr12-10408358-T-C
• rs2617170
• NM_013431.2:c.311A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013431.2(KLRC4):​c.311A>G​(p.Asn104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,466,520 control chromosomes in the GnomAD database, including 313,016 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28937 hom., cov: 31)
  • Exomes 𝑓: 0.65 (284079 hom.)
• Consequence: KLRC4 NM_013431.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06
• Publications: 90 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.9274346E-6).
• BP6: Variant 12-10408358-T-C is Benign according to our data. Variant chr12-10408358-T-C is described in ClinVar as Benign. ClinVar VariationId is 1273274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC4	NM_013431.2	c.311A>G	p.Asn104Ser	missense_variant	Exon 3 of 4	ENST00000309384.3	NP_038459.1
KLRC4-KLRK1	NM_001199805.1	c.-364A>G		5_prime_UTR_variant	Exon 3 of 13		NP_001186734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLRC4	ENST00000309384.3	c.311A>G	p.Asn104Ser	missense_variant	Exon 3 of 4	1	NM_013431.2	ENSP00000310216.1
KLRC4-KLRK1	ENST00000539300.5	n.284A>G		non_coding_transcript_exon_variant	Exon 3 of 13	2		ENSP00000455951.1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92590 AN: 151732 Hom.: 28918 Cov.: 31

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.628 AC: 148250 AN: 236222 AF XY: 0.627

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.652

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.662

GnomAD4 exome AF: 0.653 AC: 858921 AN: 1314668 Hom.: 284079 Cov.: 21 AF XY: 0.652 AC XY: 430251 AN XY: 660390

African (AFR) AF: 0.446 AC: 13546 AN: 30368

American (AMR) AF: 0.646 AC: 26738 AN: 41386

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 14890 AN: 25054

East Asian (EAS) AF: 0.574 AC: 21716 AN: 37826

South Asian (SAS) AF: 0.550 AC: 44457 AN: 80792

European-Finnish (FIN) AF: 0.653 AC: 34514 AN: 52872

Middle Eastern (MID) AF: 0.624 AC: 3404 AN: 5458

European-Non Finnish (NFE) AF: 0.675 AC: 665252 AN: 985524

Other (OTH) AF: 0.621 AC: 34404 AN: 55388

GnomAD4 genome AF: 0.610 AC: 92657 AN: 151852 Hom.: 28937 Cov.: 31 AF XY: 0.608 AC XY: 45140 AN XY: 74202

African (AFR) AF: 0.471 AC: 19486 AN: 41394

American (AMR) AF: 0.670 AC: 10216 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2073 AN: 3466

East Asian (EAS) AF: 0.559 AC: 2888 AN: 5168

South Asian (SAS) AF: 0.550 AC: 2641 AN: 4804

European-Finnish (FIN) AF: 0.648 AC: 6820 AN: 10530

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46473 AN: 67914

Other (OTH) AF: 0.612 AC: 1294 AN: 2116

Alfa AF: 0.657 Hom.: 152070

Bravo AF: 0.604

TwinsUK AF: 0.687 AC: 2546

ALSPAC AF: 0.688 AC: 2653

ESP6500AA AF: 0.478 AC: 2102

ESP6500EA AF: 0.679 AC: 5820

ExAC AF: 0.628 AC: 76173

Asia WGS AF: 0.562 AC: 1937 AN: 3442

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23291587, 25203601) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.93
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0000039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.071
Sift	Benign	0.091	T
Sift4G	Benign	0.11	T
Polyphen		0.15	B
Vest4		0.014
MPC		0.27
ClinPred		0.0082	T
GERP RS		2.9
Varity_R		0.059
gMVP		0.068
Mutation Taster		=98/2	polymorphism (auto)

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: rs2617170; hg19: chr12-10560957; COSMIC: COSV58671646; COSMIC: COSV58671646;