dbSNP rs193922734: WNK4:p.Glu560Gly (chr17-42787480-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_032387.5(WNK4):c.1679A>G(p.Glu560Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WNK4
NM_032387.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.27

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_032387.5

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK4	NM_032387.5 link	c.1679A>G	p.Glu560Gly	missense_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.1679A>G	p.Glu560Gly	missense_variant	Exon 7 of 19	1	NM_032387.5	ENSP00000246914.4		Q96J92-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1251698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

621176

African (AFR)

AF:

0.00

AC:

AN:

29270

American (AMR)

AF:

0.00

AC:

AN:

38472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18234

East Asian (EAS)

AF:

0.00

AC:

AN:

21166

South Asian (SAS)

AF:

0.00

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

974240

Other (OTH)

AF:

0.00

AC:

AN:

46704

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2B

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.6

PhyloP100

7.3

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.50

MutPred

0.25

Loss of stability (P = 0.0518);

MVP

0.97

MPC

0.20

ClinPred

0.98

GERP RS

5.0

Varity_R

0.87

gMVP

0.61

Mutation Taster

=72/28

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over