17-42796301-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032387.5(WNK4):c.3610C>T(p.Arg1204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,612,510 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 25 hom. )

Consequence

WNK4
NM_032387.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.65

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008295596).

BP6

Variant 17-42796301-C-T is Benign according to our data. Variant chr17-42796301-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 323355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 703 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK4	NM_032387.5 link	c.3610C>T	p.Arg1204Cys	missense_variant	Exon 17 of 19	ENST00000246914.10	NP_115763.2	Q96J92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WNK4	ENST00000246914.10 link	c.3610C>T	p.Arg1204Cys	missense_variant	Exon 17 of 19	1	NM_032387.5	ENSP00000246914.4	Q96J92-1
WNK4	ENST00000591448.5 link	n.*2111C>T		non_coding_transcript_exon_variant	Exon 16 of 18	1		ENSP00000467088.1	K7ENT7
WNK4	ENST00000591448.5 link	n.*2111C>T		3_prime_UTR_variant	Exon 16 of 18	1		ENSP00000467088.1	K7ENT7
COA3	ENST00000586680.1 link	n.*143-148G>A		intron_variant	Intron 2 of 2	2		ENSP00000467546.1	K7EPV0

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

705

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0289

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00467

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00573

AC:

1388

AN:

242124

Hom.:

AF XY:

0.00562

AC XY:

743

AN XY:

132172

show subpopulations

Gnomad AFR exome

AF:

0.000412

Gnomad AMR exome

AF:

0.000970

Gnomad ASJ exome

AF:

0.00355

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00564

Gnomad FIN exome

AF:

0.0258

Gnomad NFE exome

AF:

0.00533

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00446

AC:

6516

AN:

1460178

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

3259

AN XY:

726334

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000877

Gnomad4 ASJ exome

AF:

0.00280

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00518

Gnomad4 FIN exome

AF:

0.0241

Gnomad4 NFE exome

AF:

0.00392

Gnomad4 OTH exome

AF:

0.00459

GnomAD4 genome

AF:

0.00461

AC:

703

AN:

152332

Hom.:

Cov.:

AF XY:

0.00567

AC XY:

422

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0289

Gnomad4 NFE

AF:

0.00466

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000458

AC:

ESP6500EA

AF:

0.00292

AC:

ExAC

AF:

0.00544

AC:

660

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WNK4: BS2 -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism type 2B

Benign:1

Mar 06, 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

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0083

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.77

MVP

0.88

MPC

0.82

ClinPred

0.011

GERP RS

3.9

Varity_R

0.38

gMVP

0.47

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