rs12828016

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018979.4(WNK1):c.5424G>T(p.Met1808Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,612,936 control chromosomes in the GnomAD database, including 123,394 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1808V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.41 ( 13066 hom., cov: 32)

Exomes 𝑓: 0.39 ( 110328 hom. )

Consequence

WNK1
NM_018979.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.446

Publications

64 publications found

Variant links:

Genes affected

WNK1 (HGNC:14540): (WNK lysine deficient protein kinase 1) This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.[provided by RefSeq, May 2010]

WNK1 Gene-Disease associations (from GenCC):

neuropathy, hereditary sensory and autonomic, type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
pseudohypoaldosteronism type 2C
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary sensory and autonomic neuropathy type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WNK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.491094E-5).

BP6

Variant 12-889199-G-T is Benign according to our data. Variant chr12-889199-G-T is described in ClinVar as [Benign]. Clinvar id is 261073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.6180G>T	p.Met2060Ile	missense_variant	Exon 21 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.5424G>T	p.Met1808Ile	missense_variant	Exon 21 of 28	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 link	c.6180G>T	p.Met2060Ile	missense_variant	Exon 21 of 28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.5424G>T	p.Met1808Ile	missense_variant	Exon 21 of 28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.407

AC:

61765

AN:

151874

Hom.:

13054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.505

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.286

Gnomad SAS

AF:

0.462

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.429

GnomAD2 exomes

AF:

0.370

AC:

92947

AN:

251292

AF XY:

0.375

show subpopulations

Gnomad AFR exome

AF:

0.513

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.279

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.398

GnomAD4 exome

AF:

0.386

AC:

563448

AN:

1460944

Hom.:

110328

Cov.:

AF XY:

0.388

AC XY:

281819

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.511

AC:

17090

AN:

33452

American (AMR)

AF:

0.294

AC:

13167

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

10691

AN:

26116

East Asian (EAS)

AF:

0.323

AC:

12820

AN:

39672

South Asian (SAS)

AF:

0.446

AC:

38452

AN:

86236

European-Finnish (FIN)

AF:

0.290

AC:

15472

AN:

53384

Middle Eastern (MID)

AF:

0.490

AC:

2824

AN:

5768

European-Non Finnish (NFE)

AF:

0.386

AC:

429418

AN:

1111228

Other (OTH)

AF:

0.390

AC:

23514

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

18399

36798

55198

73597

91996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.407

AC:

61814

AN:

151992

Hom.:

13066

Cov.:

AF XY:

0.401

AC XY:

29825

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.505

AC:

20910

AN:

41412

American (AMR)

AF:

0.341

AC:

5215

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

1436

AN:

3466

East Asian (EAS)

AF:

0.286

AC:

1478

AN:

5168

South Asian (SAS)

AF:

0.461

AC:

2225

AN:

4826

European-Finnish (FIN)

AF:

0.283

AC:

2989

AN:

10566

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.387

AC:

26269

AN:

67966

Other (OTH)

AF:

0.432

AC:

909

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1869

3739

5608

7478

9347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.395

Hom.:

61363

Bravo

AF:

0.412

TwinsUK

AF:

0.394

AC:

1462

ALSPAC

AF:

0.384

AC:

1480

ESP6500AA

AF:

0.510

AC:

2248

ESP6500EA

AF:

0.391

AC:

3363

ExAC

AF:

0.377

AC:

45722

Asia WGS

AF:

0.412

AC:

1433

AN:

3478

EpiCase

AF:

0.408

EpiControl

AF:

0.404

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoaldosteronism type 2C

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. -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.060

T;.;T;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.077

T;T;T;T;T

MetaRNN

Benign

0.000025

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.69

.;.;N;.;.

PhyloP100

-0.45

PrimateAI

Benign

0.36

PROVEAN

Benign

0.19

N;.;N;.;N

REVEL

Benign

0.011

Sift

Benign

0.21

T;.;T;.;T

Sift4G

Benign

0.43

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.086

MutPred

0.28

.;.;Loss of catalytic residue at M1808 (P = 0.0215);.;.;

MPC

0.13

ClinPred

0.0011

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs12828016

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