chr12-890472-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_213655.5(WNK1):c.6224C>T(p.Pro2075Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,614,040 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 31)

Exomes 𝑓: 0.013 ( 234 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.88

Publications

16 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=0.0032887757).

BP6

Variant 12-890472-C-T is Benign according to our data. Variant chr12-890472-C-T is described in ClinVar as Benign. ClinVar VariationId is 310836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0106 (1617/152228) while in subpopulation SAS AF = 0.055 (265/4822). AF 95% confidence interval is 0.0495. There are 19 homozygotes in GnomAd4. There are 889 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.6224C>T	p.Pro2075Leu	missense_variant	Exon 22 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.5468C>T	p.Pro1823Leu	missense_variant	Exon 22 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.6224C>T	p.Pro2075Leu	missense_variant	Exon 22 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.5468C>T	p.Pro1823Leu	missense_variant	Exon 22 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1620

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.00668

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.0549

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0165

AC:

4146

AN:

251436

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0329

Gnomad EAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.0151

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0132

AC:

19248

AN:

1461812

Hom.:

234

Cov.:

AF XY:

0.0145

AC XY:

10520

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33480

American (AMR)

AF:

0.00534

AC:

239

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0336

AC:

878

AN:

26132

East Asian (EAS)

AF:

0.0134

AC:

530

AN:

39694

South Asian (SAS)

AF:

0.0472

AC:

4068

AN:

86252

European-Finnish (FIN)

AF:

0.0139

AC:

744

AN:

53416

Middle Eastern (MID)

AF:

0.0348

AC:

201

AN:

5768

European-Non Finnish (NFE)

AF:

0.0103

AC:

11475

AN:

1111954

Other (OTH)

AF:

0.0173

AC:

1046

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1048

2096

3143

4191

5239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.0106

AC:

1617

AN:

152228

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

889

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41538

American (AMR)

AF:

0.00667

AC:

102

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

113

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5178

South Asian (SAS)

AF:

0.0550

AC:

265

AN:

4822

European-Finnish (FIN)

AF:

0.0138

AC:

146

AN:

10598

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

741

AN:

68014

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0116

Hom.:

Bravo

AF:

0.00888

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0129

AC:

111

ExAC

AF:

0.0167

AC:

2031

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WNK1: BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 31, 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

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.13

T;.;D;.;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;M;.;.

PhyloP100

3.9

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.3

D;.;D;.;D

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;.;D;.;D

Sift4G

Uncertain

0.030

D;.;D;D;D

Vest4

0.40

ClinPred

0.051

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.11

gMVP

0.12

Mutation Taster

=98/2

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

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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