rs956868

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_213655.5(WNK1):c.3922A>C(p.Thr1308Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,940 control chromosomes in the GnomAD database, including 575,538 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1308T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.84 ( 53881 hom., cov: 31)

Exomes 𝑓: 0.84 ( 521657 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0690

Publications

58 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=7.2372313E-7).

BP6

Variant 12-881746-A-C is Benign according to our data. Variant chr12-881746-A-C is described in ClinVar as Benign. ClinVar VariationId is 261070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.3922A>C	p.Thr1308Pro	missense_variant	Exon 13 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.3166A>C	p.Thr1056Pro	missense_variant	Exon 13 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.3922A>C	p.Thr1308Pro	missense_variant	Exon 13 of 28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.3166A>C	p.Thr1056Pro	missense_variant	Exon 13 of 28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.841

AC:

127863

AN:

152010

Hom.:

53836

Cov.:

show subpopulations

Gnomad AFR

AF:

0.856

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.863

Gnomad ASJ

AF:

0.844

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.847

Gnomad OTH

AF:

0.847

GnomAD2 exomes

AF:

0.832

AC:

209232

AN:

251432

AF XY:

0.831

show subpopulations

Gnomad AFR exome

AF:

0.859

Gnomad AMR exome

AF:

0.865

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.807

Gnomad FIN exome

AF:

0.739

Gnomad NFE exome

AF:

0.841

Gnomad OTH exome

AF:

0.826

GnomAD4 exome

AF:

0.844

AC:

1234188

AN:

1461812

Hom.:

521657

Cov.:

AF XY:

0.843

AC XY:

613179

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.857

AC:

28683

AN:

33478

American (AMR)

AF:

0.866

AC:

38713

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.845

AC:

22087

AN:

26136

East Asian (EAS)

AF:

0.839

AC:

33323

AN:

39696

South Asian (SAS)

AF:

0.823

AC:

70967

AN:

86258

European-Finnish (FIN)

AF:

0.746

AC:

39825

AN:

53410

Middle Eastern (MID)

AF:

0.768

AC:

4432

AN:

5768

European-Non Finnish (NFE)

AF:

0.850

AC:

945586

AN:

1111950

Other (OTH)

AF:

0.837

AC:

50572

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

11248

22497

33745

44994

56242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21192

42384

63576

84768

105960

<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:

0.841

AC:

127963

AN:

152128

Hom.:

53881

Cov.:

AF XY:

0.838

AC XY:

62286

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.856

AC:

35490

AN:

41482

American (AMR)

AF:

0.863

AC:

13202

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.844

AC:

2929

AN:

3470

East Asian (EAS)

AF:

0.817

AC:

4229

AN:

5178

South Asian (SAS)

AF:

0.830

AC:

3998

AN:

4814

European-Finnish (FIN)

AF:

0.735

AC:

7763

AN:

10564

Middle Eastern (MID)

AF:

0.769

AC:

226

AN:

294

European-Non Finnish (NFE)

AF:

0.847

AC:

57607

AN:

68008

Other (OTH)

AF:

0.848

AC:

1793

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1042

2085

3127

4170

5212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.847

Hom.:

193009

Bravo

AF:

0.851

TwinsUK

AF:

0.856

AC:

3175

ALSPAC

AF:

0.855

AC:

3296

ESP6500AA

AF:

0.855

AC:

3768

ESP6500EA

AF:

0.851

AC:

7321

ExAC

AF:

0.831

AC:

100941

Asia WGS

AF:

0.838

AC:

2915

AN:

3478

EpiCase

AF:

0.845

EpiControl

AF:

0.842

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:3

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17000706) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Pseudohypoaldosteronism type 2C

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. -

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

0.043

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.8

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.061

T;.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.15

T;T;T;T;T

MetaRNN

Benign

7.2e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

.;.;N;.;.

PhyloP100

-0.069

PrimateAI

Benign

0.29

PROVEAN

Benign

2.7

N;.;N;.;N

REVEL

Benign

0.053

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.34

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.036

MPC

0.15

ClinPred

0.0012

GERP RS

0.64

PromoterAI

-0.0064

Neutral

(source)

Varity_R

0.045

gMVP

0.067

Mutation Taster

=97/3

polymorphism (auto)

(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

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

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