Genetic Variant WNK3:p.Tyr1742Cys (chrX-54198502-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000354646.7(WNK3):c.5225A>G(p.Tyr1742Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,207,078 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

WNK3
ENST00000354646.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56

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: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
WNK3	NM_020922.5 link	c.5225A>G	p.Tyr1742Cys	missense_variant	Exon 24 of 24	NP_065973.2	Q9BYP7-1
WNK3	NM_001002838.4 link	c.5054A>G	p.Tyr1685Cys	missense_variant	Exon 23 of 23	NP_001002838.1	Q9BYP7-3
WNK3	NM_001395166.1 link	c.5054A>G	p.Tyr1685Cys	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.5225A>G	p.Tyr1742Cys	missense_variant	Exon 24 of 24	1		ENSP00000346667.2		Q9BYP7-1
WNK3	ENST00000375169.7 link	c.5054A>G	p.Tyr1685Cys	missense_variant	Exon 23 of 23	5		ENSP00000364312.3		Q9BYP7-3

Frequencies

GnomAD3 genomes

AF:

0.00000914

AC:

AN:

109457

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183123

AF XY:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1097621

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363013

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26387

American (AMR)

AF:

0.00

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54085

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000178

AC:

AN:

841632

Other (OTH)

AF:

0.00

AC:

AN:

46071

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000914

AC:

AN:

109457

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31757

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30083

American (AMR)

AF:

0.00

AC:

AN:

10105

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2623

East Asian (EAS)

AF:

0.00

AC:

AN:

3477

South Asian (SAS)

AF:

0.00

AC:

AN:

2432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5725

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52637

Other (OTH)

AF:

0.00

AC:

AN:

1454

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 04, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T;T;.

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.87

D;D;.;D

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.7

.;M;M;.

PhyloP100

2.6

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.3

D;D;D;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.58

MutPred

0.35

.;Loss of phosphorylation at Y1742 (P = 0.0573);Loss of phosphorylation at Y1742 (P = 0.0573);.;

MVP

0.93

MPC

0.77

ClinPred

0.94

GERP RS

5.5

Varity_R

0.45

gMVP

0.63

Mutation Taster

=96/4

polymorphism

(source)

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

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X-54198502-T-C

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