12-885321-G-C

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.5273G>C(p.Cys1758Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,172 control chromosomes in the GnomAD database, including 803,547 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. C1758P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.99 ( 74464 hom., cov: 31)

Exomes 𝑓: 1.0 ( 729083 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.753

Publications

37 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=9.164664E-7).

BP6

Variant 12-885321-G-C is Benign according to our data. Variant chr12-885321-G-C is described in ClinVar as Benign. ClinVar VariationId is 261072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.5273G>C	p.Cys1758Ser	missense_variant	Exon 19 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.4517G>C	p.Cys1506Ser	missense_variant	Exon 19 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.5273G>C	p.Cys1758Ser	missense_variant	Exon 19 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.4517G>C	p.Cys1506Ser	missense_variant	Exon 19 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.989

AC:

150466

AN:

152176

Hom.:

74414

Cov.:

show subpopulations

Gnomad AFR

AF:

0.961

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.996

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.992

GnomAD2 exomes

AF:

0.997

AC:

250314

AN:

251096

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.960

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.998

GnomAD4 exome

AF:

0.999

AC:

1459989

AN:

1461878

Hom.:

729083

Cov.:

AF XY:

0.999

AC XY:

726409

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.958

AC:

32087

AN:

33480

American (AMR)

AF:

0.997

AC:

44580

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26135

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39700

AN:

39700

South Asian (SAS)

AF:

1.00

AC:

86245

AN:

86256

European-Finnish (FIN)

AF:

1.00

AC:

53410

AN:

53410

Middle Eastern (MID)

AF:

0.997

AC:

5753

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111836

AN:

1112008

Other (OTH)

AF:

0.997

AC:

60243

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

131

262

394

525

656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21672

43344

65016

86688

108360

<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:

0.989

AC:

150575

AN:

152294

Hom.:

74464

Cov.:

AF XY:

0.989

AC XY:

73667

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.961

AC:

39928

AN:

41546

American (AMR)

AF:

0.996

AC:

15228

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5180

AN:

5180

South Asian (SAS)

AF:

1.00

AC:

4824

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68025

AN:

68040

Other (OTH)

AF:

0.992

AC:

2098

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.957

Hom.:

54593

Bravo

AF:

0.987

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.959

AC:

4225

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

0.996

AC:

120968

Asia WGS

AF:

0.998

AC:

3472

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:2

Jun 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

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 13, 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

0.051

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.1

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.065

T;.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.027

T;T;T;T;T

MetaRNN

Benign

9.2e-7

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

.;.;N;.;.

PhyloP100

0.75

PrimateAI

Benign

0.32

PROVEAN

Benign

2.9

N;.;N;.;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.87

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.043

MutPred

0.24

.;.;Gain of glycosylation at C1506 (P = 0.0182);.;.;

MPC

0.15

ClinPred

0.0014

GERP RS

5.3

Varity_R

0.031

gMVP

0.038

Mutation Taster

=98/2

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

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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