chrX-54198512-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000354646.7(WNK3):c.5215G>A(p.Val1739Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,204,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000077 ( 0 hom. 39 hem. )

Consequence

WNK3
ENST00000354646.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Prieto syndrome
Inheritance: XL Classification: MODERATE Submitted by: G2P

WNK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.062177956).

BS2

High Hemizygotes in GnomAdExome4 at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
WNK3	NM_020922.5 link	c.5215G>A	p.Val1739Ile	missense_variant	Exon 24 of 24	NP_065973.2	Q9BYP7-1
WNK3	NM_001002838.4 link	c.5044G>A	p.Val1682Ile	missense_variant	Exon 23 of 23	NP_001002838.1	Q9BYP7-3
WNK3	NM_001395166.1 link	c.5044G>A	p.Val1682Ile	missense_variant	Exon 23 of 23	NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7 link	c.5215G>A	p.Val1739Ile	missense_variant	Exon 24 of 24	1		ENSP00000346667.2		Q9BYP7-1
WNK3	ENST00000375169.7 link	c.5044G>A	p.Val1682Ile	missense_variant	Exon 23 of 23	5		ENSP00000364312.3		Q9BYP7-3

Frequencies

GnomAD3 genomes

AF:

0.0000184

AC:

AN:

108767

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000381

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

182936

AF XY:

0.000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000978

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000767

AC:

AN:

1095441

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

361143

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26343

American (AMR)

AF:

0.0000284

AC:

AN:

35167

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30173

South Asian (SAS)

AF:

0.000872

AC:

AN:

53927

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40500

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.0000286

AC:

AN:

839847

Other (OTH)

AF:

0.000239

AC:

AN:

45996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000184

AC:

AN:

108767

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

31329

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29822

American (AMR)

AF:

0.00

AC:

AN:

9971

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2619

East Asian (EAS)

AF:

0.00

AC:

AN:

3464

South Asian (SAS)

AF:

0.00

AC:

AN:

2430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

52488

Other (OTH)

AF:

0.00

AC:

AN:

1443

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5215G>A (p.V1739I) alteration is located in exon 24 (coding exon 23) of the WNK3 gene. This alteration results from a G to A substitution at nucleotide position 5215, causing the valine (V) at amino acid position 1739 to be replaced by an isoleucine (I). 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

0.080

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

.;T;T;.

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.71

T;T;.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.062

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

.;M;M;.

PhyloP100

2.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.32

N;N;N;.

REVEL

Benign

0.078

Sift

Uncertain

0.0020

D;D;D;.

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.94

P;P;P;.

Vest4

0.13

MutPred

0.17

.;Loss of catalytic residue at V1739 (P = 0.0719);Loss of catalytic residue at V1739 (P = 0.0719);.;

MVP

0.16

MPC

0.17

ClinPred

0.12

GERP RS

5.5

Varity_R

0.23

gMVP

0.089

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chrX-54198512-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over