17-42787442-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032387.5(WNK4):c.1641C>T(p.Ala547Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,842 control chromosomes in the GnomAD database, including 2,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 1231 hom., cov: 32)

Exomes 𝑓: 0.016 ( 1668 hom. )

Consequence

WNK4
NM_032387.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.202

Publications

9 publications found

Variant links:

Genes affected

WNK4 (HGNC:14544): (WNK lysine deficient protein kinase 4) This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

WNK4 Gene-Disease associations (from GenCC):

pseudohypoaldosteronism type 2B
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

WNK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 17-42787442-C-T is Benign according to our data. Variant chr17-42787442-C-T is described in ClinVar as Benign. ClinVar VariationId is 323323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.202 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK4	NM_032387.5 link	c.1641C>T	p.Ala547Ala	synonymous_variant	Exon 7 of 19	ENST00000246914.10	NP_115763.2	Q96J92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK4	ENST00000246914.10 link	c.1641C>T	p.Ala547Ala	synonymous_variant	Exon 7 of 19	1	NM_032387.5	ENSP00000246914.4		Q96J92-1

Frequencies

GnomAD3 genomes

AF:

0.0734

AC:

11148

AN:

151876

Hom.:

1217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.0425

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.0547

GnomAD2 exomes

AF:

0.0360

AC:

9040

AN:

251344

AF XY:

0.0351

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.0446

Gnomad FIN exome

AF:

0.00501

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0157

AC:

23011

AN:

1461848

Hom.:

1668

Cov.:

AF XY:

0.0176

AC XY:

12774

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.235

AC:

7877

AN:

33480

American (AMR)

AF:

0.0179

AC:

802

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

272

AN:

26136

East Asian (EAS)

AF:

0.0391

AC:

1553

AN:

39698

South Asian (SAS)

AF:

0.100

AC:

8641

AN:

86258

European-Finnish (FIN)

AF:

0.00525

AC:

280

AN:

53384

Middle Eastern (MID)

AF:

0.0189

AC:

109

AN:

5768

European-Non Finnish (NFE)

AF:

0.00150

AC:

1665

AN:

1112006

Other (OTH)

AF:

0.0300

AC:

1812

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

1486

2973

4459

5946

7432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0737

AC:

11206

AN:

151994

Hom.:

1231

Cov.:

AF XY:

0.0734

AC XY:

5452

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.234

AC:

9684

AN:

41384

American (AMR)

AF:

0.0298

AC:

455

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.0428

AC:

221

AN:

5162

South Asian (SAS)

AF:

0.105

AC:

505

AN:

4796

European-Finnish (FIN)

AF:

0.00462

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

67980

Other (OTH)

AF:

0.0541

AC:

114

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

421

842

1262

1683

2104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0291

Hom.:

1283

Bravo

AF:

0.0799

Asia WGS

AF:

0.0820

AC:

285

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00219

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 15, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pseudohypoaldosteronism type 2B

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.5

(source)

DANN

Benign

0.38

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(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

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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