12-10408993-C-G

Position:

chr12-10408993-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013431.2(KLRC4):c.205G>C(p.Glu69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

KLRC4
NM_013431.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

Variant links:

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 links:

KLRC4-KLRK1 (HGNC:):

KLRC4-KLRK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06243038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRC4	NM_013431.2 linkuse as main transcript	c.205G>C	p.Glu69Gln	missense_variant	2/4	ENST00000309384.3	NP_038459.1
KLRC4-KLRK1	NM_001199805.1 linkuse as main transcript	c.-470G>C		5_prime_UTR_variant	2/13		NP_001186734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRC4	ENST00000309384.3 linkuse as main transcript	c.205G>C	p.Glu69Gln	missense_variant	2/4	1	NM_013431.2	ENSP00000310216	P1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251096

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000190

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Bravo

AF:

0.000223

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.205G>C (p.E69Q) alteration is located in exon 2 (coding exon 2) of the KLRC4 gene. This alteration results from a G to C substitution at nucleotide position 205, causing the glutamic acid (E) at amino acid position 69 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.088

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0012

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.9

REVEL

Benign

0.088

Sift

Benign

0.033

Sift4G

Uncertain

0.046

Polyphen

1.0

Vest4

0.21

MVP

0.54

MPC

0.86

ClinPred

0.078

GERP RS

1.3

Varity_R

0.083

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over