17-42796301-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:4

Conservation

PhyloP100: 2.65

Publications

7 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 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 Gene-Disease associations (from GenCC):

cytochrome-c oxidase deficiency disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial disease
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
mitochondrial complex IV deficiency, nuclear type 14
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

COA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 323355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 703 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032387.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK4	NM_032387.5	MANE Select	c.3610C>T	p.Arg1204Cys	missense	Exon 17 of 19	NP_115763.2
	WNK4	NM_001321299.2		c.2602C>T	p.Arg868Cys	missense	Exon 16 of 18	NP_001308228.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WNK4	ENST00000246914.10	TSL:1 MANE Select	c.3610C>T	p.Arg1204Cys	missense	Exon 17 of 19	ENSP00000246914.4
WNK4	ENST00000591448.5	TSL:1	n.*2111C>T		non_coding_transcript_exon	Exon 16 of 18	ENSP00000467088.1
WNK4	ENST00000591448.5	TSL:1	n.*2111C>T		3_prime_UTR	Exon 16 of 18	ENSP00000467088.1

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

GnomAD2 exomes

AF:

0.00573

AC:

1388

AN:

242124

AF XY:

0.00562

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 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

African (AFR)

AF:

0.000538

AC:

AN:

33444

American (AMR)

AF:

0.000877

AC:

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.00280

AC:

AN:

26086

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39638

South Asian (SAS)

AF:

0.00518

AC:

446

AN:

86066

European-Finnish (FIN)

AF:

0.0241

AC:

1278

AN:

53054

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00392

AC:

4358

AN:

1111364

Other (OTH)

AF:

0.00459

AC:

277

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

439

878

1317

1756

2195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.00461

AC:

703

AN:

152332

Hom.:

Cov.:

AF XY:

0.00567

AC XY:

422

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41578

American (AMR)

AF:

0.000784

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00580

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0289

AC:

307

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00466

AC:

317

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00317

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Pseudohypoaldosteronism type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

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

PhyloP100

2.6

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

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over