dbSNP rs756781927: KLRC3:p.Cys145Ser (chr12-10418396-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002261.3(KLRC3):c.434G>C(p.Cys145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KLRC3
NM_002261.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.70

Variant links:

Genes affected

KLRC3 (HGNC:6376): (killer cell lectin like receptor C3) 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. KLRC3 is a member of the NKG2 group which are expressed primarily in natural killer (NK) cells and encodes a family of transmembrane proteins characterized by a type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. The NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

KLRC3 links:

ENSG00000255641 (HGNC:):

ENSG00000255641 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLRC3	NM_002261.3 link	c.434G>C	p.Cys145Ser	missense_variant	Exon 4 of 7	ENST00000396439.7	NP_002252.2	Q07444-1
KLRC3	NM_007333.2 link	c.434G>C	p.Cys145Ser	missense_variant	Exon 4 of 6		NP_031359.2	Q07444-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLRC3	ENST00000396439.7 link	c.434G>C	p.Cys145Ser	missense_variant	Exon 4 of 7	5	NM_002261.3	ENSP00000379716.3	Q07444-1
KLRC3	ENST00000381903.2 link	c.434G>C	p.Cys145Ser	missense_variant	Exon 4 of 6	1		ENSP00000371328.2	Q07444-2
ENSG00000255641	ENST00000539033.1 link	c.434G>C	p.Cys145Ser	missense_variant	Exon 4 of 7	1		ENSP00000437563.1	F5H6K3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459986

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726402

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.28

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

-0.037

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.9

H;H;.

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-9.2

D;D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.77

MutPred

0.77

Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);

MVP

0.40

MPC

0.91, 0.40

ClinPred

1.0

GERP RS

2.3

Varity_R

0.97

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over