Genetic Variant KLRC4:p.Gly63Asp (chr12-10409010-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013431.2(KLRC4):c.188G>A(p.Gly63Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G63V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KLRC4
NM_013431.2 missense, splice_region

Scores

Splicing: ADA: 0.00008457

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.87

Publications

0 publications found

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: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]

KLRC4-KLRK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040745795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013431.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLRC4	NM_013431.2	MANE Select	c.188G>A	p.Gly63Asp	missense splice_region	Exon 2 of 4	NP_038459.1	O43908
KLRC4-KLRK1	NM_001199805.1		c.-487G>A		splice_region	Exon 2 of 13	NP_001186734.1	P26718-1
KLRC4-KLRK1	NM_001199805.1		c.-487G>A		5_prime_UTR	Exon 2 of 13	NP_001186734.1	P26718-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLRC4	ENST00000309384.3	TSL:1 MANE Select	c.188G>A	p.Gly63Asp	missense splice_region	Exon 2 of 4	ENSP00000310216.1	O43908
KLRC4-KLRK1	ENST00000539300.5	TSL:2	n.161G>A		splice_region non_coding_transcript_exon	Exon 2 of 13	ENSP00000455951.1	H3BQV0
KLRC4	ENST00000718241.1		c.188G>A	p.Gly63Asp	missense splice_region	Exon 2 of 4	ENSP00000520686.1	O43908

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.12

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.0068

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.29

M_CAP

Benign

0.00084

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.41

PhyloP100

-1.9

PrimateAI

Benign

0.24

PROVEAN

Benign

0.77

REVEL

Benign

0.045

Sift

Benign

0.68

Sift4G

Benign

0.74

Polyphen

0.63

Vest4

0.054

MutPred

0.47

Gain of catalytic residue at P66 (P = 8e-04)

MVP

0.21

MPC

0.31

ClinPred

0.13

GERP RS

-2.1

Varity_R

0.031

gMVP

0.062

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000085

dbscSNV1_RF

Benign

0.088

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over