12-908031-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_213655.5(WNK1):c.7584C>T(p.Tyr2528Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,094 control chromosomes in the GnomAD database, including 803,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74531 hom., cov: 31)

Exomes 𝑓: 1.0 ( 729078 hom. )

Consequence

WNK1
NM_213655.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.732

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-908031-C-T is Benign according to our data. Variant chr12-908031-C-T is described in ClinVar as Benign. ClinVar VariationId is 261074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.732 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.7584C>T	p.Tyr2528Tyr	synonymous_variant	Exon 27 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.6828C>T	p.Tyr2276Tyr	synonymous_variant	Exon 27 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.7584C>T	p.Tyr2528Tyr	synonymous_variant	Exon 27 of 28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.6828C>T	p.Tyr2276Tyr	synonymous_variant	Exon 27 of 28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.989

AC:

150555

AN:

152206

Hom.:

74481

Cov.:

show subpopulations

Gnomad AFR

AF:

0.962

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:

0.993

GnomAD2 exomes

AF:

0.997

AC:

247723

AN:

248478

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.962

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:

1459929

AN:

1461770

Hom.:

729078

Cov.:

AF XY:

0.999

AC XY:

726378

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.960

AC:

32129

AN:

33478

American (AMR)

AF:

0.997

AC:

44580

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26135

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39698

AN:

39698

South Asian (SAS)

AF:

1.00

AC:

86245

AN:

86258

European-Finnish (FIN)

AF:

1.00

AC:

53310

AN:

53310

Middle Eastern (MID)

AF:

0.997

AC:

5753

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111838

AN:

1112006

Other (OTH)

AF:

0.997

AC:

60241

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

107

213

320

426

533

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:

150664

AN:

152324

Hom.:

74531

Cov.:

AF XY:

0.990

AC XY:

73719

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.962

AC:

39991

AN:

41560

American (AMR)

AF:

0.996

AC:

15237

AN:

15300

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:

4822

AN:

4822

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68032

AN:

68044

Other (OTH)

AF:

0.993

AC:

2100

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.995

Hom.:

101785

Bravo

AF:

0.987

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

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

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

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

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.45

(source)

DANN

Benign

0.77

PhyloP100

-0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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