chr12-753986-G-A

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.421G>A(p.Ala141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,591,360 control chromosomes in the GnomAD database, including 12,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. A141V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.099 ( 970 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11842 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.186

Publications

26 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=0.0025852323).

BP6

Variant 12-753986-G-A is Benign according to our data. Variant chr12-753986-G-A is described in ClinVar as Benign. ClinVar VariationId is 137927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.421G>A	p.Ala141Thr	missense_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.421G>A	p.Ala141Thr	missense_variant	Exon 1 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.421G>A	p.Ala141Thr	missense_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.421G>A	p.Ala141Thr	missense_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.0987

AC:

15015

AN:

152132

Hom.:

970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0304

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.0725

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.0584

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.0893

GnomAD2 exomes

AF:

0.123

AC:

24434

AN:

199102

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.0274

Gnomad AMR exome

AF:

0.0544

Gnomad ASJ exome

AF:

0.117

Gnomad EAS exome

AF:

0.0672

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.122

AC:

176098

AN:

1439110

Hom.:

11842

Cov.:

AF XY:

0.124

AC XY:

88734

AN XY:

714316

show subpopulations

African (AFR)

AF:

0.0264

AC:

871

AN:

32938

American (AMR)

AF:

0.0549

AC:

2238

AN:

40748

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2926

AN:

25672

East Asian (EAS)

AF:

0.0475

AC:

1829

AN:

38516

South Asian (SAS)

AF:

0.159

AC:

13417

AN:

84276

European-Finnish (FIN)

AF:

0.230

AC:

11574

AN:

50290

Middle Eastern (MID)

AF:

0.170

AC:

963

AN:

5670

European-Non Finnish (NFE)

AF:

0.123

AC:

135048

AN:

1101514

Other (OTH)

AF:

0.122

AC:

7232

AN:

59486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

10771

21542

32312

43083

53854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4854

9708

14562

19416

24270

<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:

0.0986

AC:

15015

AN:

152250

Hom.:

970

Cov.:

AF XY:

0.104

AC XY:

7727

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0304

AC:

1264

AN:

41548

American (AMR)

AF:

0.0724

AC:

1109

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

389

AN:

3468

East Asian (EAS)

AF:

0.0586

AC:

303

AN:

5174

South Asian (SAS)

AF:

0.147

AC:

710

AN:

4820

European-Finnish (FIN)

AF:

0.241

AC:

2560

AN:

10602

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.123

AC:

8348

AN:

68008

Other (OTH)

AF:

0.0879

AC:

186

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

699

1398

2097

2796

3495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.109

Hom.:

655

Bravo

AF:

0.0809

TwinsUK

AF:

0.124

AC:

460

ALSPAC

AF:

0.123

AC:

474

ESP6500AA

AF:

0.0255

AC:

107

ESP6500EA

AF:

0.108

AC:

896

ExAC

AF:

0.107

AC:

12721

Asia WGS

AF:

0.0920

AC:

321

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 07, 2018

Athena Diagnostics

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. -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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 03, 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

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

T;.;T;.;.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

MetaRNN

Benign

0.0026

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

.;M;M;M;M;.

PhyloP100

0.19

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

N;N;N;.;N;N

REVEL

Benign

0.086

Sift

Uncertain

0.024

D;D;D;.;D;D

Sift4G

Benign

0.55

T;.;T;T;T;T

Polyphen

0.11

B;.;B;.;.;B

Vest4

0.20

MPC

0.71

ClinPred

0.012

GERP RS

4.3

Varity_R

0.073

gMVP

0.18

Mutation Taster

=95/5

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