17-42795302-C-T

Position:

chr17-42795302-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032387.5(WNK4):c.2881C>T(p.Pro961Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,788 control chromosomes in the GnomAD database, including 2,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 1216 hom., cov: 31)

Exomes 𝑓: 0.016 ( 1664 hom. )

Consequence

WNK4
NM_032387.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.45

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 links:

COA3 (HGNC:24990): (cytochrome c oxidase assembly factor 3) This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function. [provided by RefSeq, Nov 2012]

COA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034779012).

BP6

Variant 17-42795302-C-T is Benign according to our data. Variant chr17-42795302-C-T is described in ClinVar as [Benign]. Clinvar id is 323347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK4	NM_032387.5 linkuse as main transcript	c.2881C>T	p.Pro961Ser	missense_variant	14/19	ENST00000246914.10	NP_115763.2	Q96J92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK4	ENST00000246914.10 linkuse as main transcript	c.2881C>T	p.Pro961Ser	missense_variant	14/19	1	NM_032387.5	ENSP00000246914.4		Q96J92-1

Frequencies

GnomAD3 genomes

AF:

0.0731

AC:

11102

AN:

151858

Hom.:

1202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.0432

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.0551

GnomAD3 exomes

AF:

0.0360

AC:

9012

AN:

250252

Hom.:

703

AF XY:

0.0351

AC XY:

4752

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.0447

Gnomad SAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.00490

Gnomad NFE exome

AF:

0.00193

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0156

AC:

22754

AN:

1461812

Hom.:

1664

Cov.:

AF XY:

0.0174

AC XY:

12638

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.235

Gnomad4 AMR exome

AF:

0.0179

Gnomad4 ASJ exome

AF:

0.0104

Gnomad4 EAS exome

AF:

0.0391

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.00523

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.0298

GnomAD4 genome

AF:

0.0734

AC:

11160

AN:

151976

Hom.:

1216

Cov.:

AF XY:

0.0731

AC XY:

5432

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.0295

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.0435

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.00452

Gnomad4 NFE

AF:

0.00197

Gnomad4 OTH

AF:

0.0545

Alfa

AF:

0.0164

Hom.:

292

Bravo

AF:

0.0798

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.228

AC:

1003

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.0407

AC:

4944

Asia WGS

AF:

0.0820

AC:

285

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pseudohypoaldosteronism type 2B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.25

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

REVEL

Benign

0.084

Sift

Benign

0.19

Sift4G

Benign

0.20

Polyphen

0.51

Vest4

0.059

MPC

0.17

ClinPred

0.014

GERP RS

4.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.8

Varity_R

0.056

gMVP

0.23

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. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over