12-862125-C-T

Variant names:

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.1994C>T(p.Thr665Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0659 in 1,613,962 control chromosomes in the GnomAD database, including 3,853 homozygotes. In-silico tool predicts 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. T665A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.056 ( 307 hom., cov: 32)

Exomes 𝑓: 0.067 ( 3546 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.03

Publications

39 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=0.0026575327).

BP6

Variant 12-862125-C-T is Benign according to our data. Variant chr12-862125-C-T is described in ClinVar as Benign. ClinVar VariationId is 137924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.1994C>T	p.Thr665Ile	missense_variant	Exon 8 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.1994C>T	p.Thr665Ile	missense_variant	Exon 8 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 link	c.1994C>T	p.Thr665Ile	missense_variant	Exon 8 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.1994C>T	p.Thr665Ile	missense_variant	Exon 8 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.0557

AC:

8471

AN:

152050

Hom.:

308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0668

Gnomad ASJ

AF:

0.0861

Gnomad EAS

AF:

0.0845

Gnomad SAS

AF:

0.0301

Gnomad FIN

AF:

0.0811

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0636

GnomAD2 exomes

AF:

0.0661

AC:

16604

AN:

251344

AF XY:

0.0656

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.0741

Gnomad ASJ exome

AF:

0.0826

Gnomad EAS exome

AF:

0.0928

Gnomad FIN exome

AF:

0.0865

Gnomad NFE exome

AF:

0.0717

Gnomad OTH exome

AF:

0.0820

GnomAD4 exome

AF:

0.0670

AC:

97886

AN:

1461794

Hom.:

3546

Cov.:

AF XY:

0.0665

AC XY:

48390

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0110

AC:

369

AN:

33476

American (AMR)

AF:

0.0750

AC:

3355

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

2216

AN:

26134

East Asian (EAS)

AF:

0.0797

AC:

3164

AN:

39698

South Asian (SAS)

AF:

0.0272

AC:

2344

AN:

86258

European-Finnish (FIN)

AF:

0.0828

AC:

4425

AN:

53410

Middle Eastern (MID)

AF:

0.106

AC:

609

AN:

5766

European-Non Finnish (NFE)

AF:

0.0696

AC:

77383

AN:

1111938

Other (OTH)

AF:

0.0666

AC:

4021

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

5392

10784

16176

21568

26960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2842

5684

8526

11368

14210

<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:

0.0556

AC:

8463

AN:

152168

Hom.:

307

Cov.:

AF XY:

0.0552

AC XY:

4107

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0132

AC:

548

AN:

41522

American (AMR)

AF:

0.0668

AC:

1020

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0861

AC:

299

AN:

3472

East Asian (EAS)

AF:

0.0845

AC:

438

AN:

5182

South Asian (SAS)

AF:

0.0295

AC:

142

AN:

4812

European-Finnish (FIN)

AF:

0.0811

AC:

859

AN:

10588

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0732

AC:

4978

AN:

68000

Other (OTH)

AF:

0.0629

AC:

133

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

397

794

1190

1587

1984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0701

Hom.:

1809

Bravo

AF:

0.0547

TwinsUK

AF:

0.0742

AC:

275

ALSPAC

AF:

0.0708

AC:

273

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0753

AC:

648

ExAC

AF:

0.0639

AC:

7756

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.0853

EpiControl

AF:

0.0812

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

May 02, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Jun 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic

0.85

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;D;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D;D

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;M;M;M;M

PhyloP100

7.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

D;D;D;.;D

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;D;D;.;D

Sift4G

Uncertain

0.0050

D;.;T;D;D

Polyphen

0.34

B;.;B;.;.

Vest4

0.52

MPC

0.13

ClinPred

0.030

GERP RS

5.9

PromoterAI

-0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.46

gMVP

0.16

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over