dbSNP rs782639623: WNK3:p.Arg1588Gln (chrX-54232886-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_020922.5(WNK3):c.4763G>A(p.Arg1588Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,209,206 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000082 ( 0 hom. 5 hem. )

Consequence

WNK3
NM_020922.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.52

Variant links:

Genes affected

WNK3 (HGNC:14543): (WNK lysine deficient protein kinase 3) This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

WNK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37173885).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
WNK3	NM_020922.5 link	c.4763G>A	p.Arg1588Gln	missense_variant	Exon 21 of 24	NP_065973.2	Q9BYP7-1
WNK3	NM_001002838.4 link	c.4622G>A	p.Arg1541Gln	missense_variant	Exon 21 of 23	NP_001002838.1	Q9BYP7-3
WNK3	NM_001395166.1 link	c.4622G>A	p.Arg1541Gln	missense_variant	Exon 21 of 23	NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7 link	c.4763G>A	p.Arg1588Gln	missense_variant	Exon 21 of 24	1		ENSP00000346667.2		Q9BYP7-1
WNK3	ENST00000375169.7 link	c.4622G>A	p.Arg1541Gln	missense_variant	Exon 21 of 23	5		ENSP00000364312.3		Q9BYP7-3

Frequencies

GnomAD3 genomes

AF:

0.0000360

AC:

AN:

111001

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000194

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000381

AC:

AN:

183516

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1098205

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363563

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.000114

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

842108

Other (OTH)

AF:

0.00

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000360

AC:

AN:

111001

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33209

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30532

American (AMR)

AF:

0.000194

AC:

AN:

10307

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2601

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5859

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53090

Other (OTH)

AF:

0.00

AC:

AN:

1485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4763G>A (p.R1588Q) alteration is located in exon 21 (coding exon 20) of the WNK3 gene. This alteration results from a G to A substitution at nucleotide position 4763, causing the arginine (R) at amino acid position 1588 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

.;T;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;.;D

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.1

.;M;M;.

PhyloP100

6.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.1

N;N;N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Benign

0.12

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.36

MutPred

0.28

.;Loss of methylation at R1588 (P = 0.0134);Loss of methylation at R1588 (P = 0.0134);Loss of methylation at R1588 (P = 0.0134);

MVP

0.79

MPC

0.84

ClinPred

0.38

GERP RS

4.8

Varity_R

0.44

gMVP

0.43

Mutation Taster

=97/3

polymorphism

(source)

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

Below is the list of publications found by LitVar for variant X:54232886 C>T . It may be empty.

rs782639623

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over