rs956868

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_018979.4(WNK1):c.3166A>C(p.Thr1056Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,940 control chromosomes in the GnomAD database, including 575,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 53881 hom., cov: 31)

Exomes 𝑓: 0.84 ( 521657 hom. )

Consequence

WNK1
NM_018979.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0690

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 links:

WNK1 (HGNC:):

WNK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WNK1. . Gene score misZ 2.1626 (greater than the threshold 3.09). Trascript score misZ 4.652 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory and autonomic, type 2A, hereditary sensory and autonomic neuropathy type 2, pseudohypoaldosteronism type 2C.

BP4

Computational evidence support a benign effect (MetaRNN=7.2372313E-7).

BP6

Variant 12-881746-A-C is Benign according to our data. Variant chr12-881746-A-C is described in ClinVar as [Benign]. Clinvar id is 261070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-881746-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.3922A>C	p.Thr1308Pro	missense_variant	13/28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 linkuse as main transcript	c.3166A>C	p.Thr1056Pro	missense_variant	13/28	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 linkuse as main transcript	c.3922A>C	p.Thr1308Pro	missense_variant	13/28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.3166A>C	p.Thr1056Pro	missense_variant	13/28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.841

AC:

127863

AN:

152010

Hom.:

53836

Cov.:

show subpopulations

Gnomad AFR

AF:

0.856

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.863

Gnomad ASJ

AF:

0.844

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.847

Gnomad OTH

AF:

0.847

GnomAD3 exomes

AF:

0.832

AC:

209232

AN:

251432

Hom.:

87310

AF XY:

0.831

AC XY:

112869

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.859

Gnomad AMR exome

AF:

0.865

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.807

Gnomad SAS exome

AF:

0.828

Gnomad FIN exome

AF:

0.739

Gnomad NFE exome

AF:

0.841

Gnomad OTH exome

AF:

0.826

GnomAD4 exome

AF:

0.844

AC:

1234188

AN:

1461812

Hom.:

521657

Cov.:

AF XY:

0.843

AC XY:

613179

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.857

Gnomad4 AMR exome

AF:

0.866

Gnomad4 ASJ exome

AF:

0.845

Gnomad4 EAS exome

AF:

0.839

Gnomad4 SAS exome

AF:

0.823

Gnomad4 FIN exome

AF:

0.746

Gnomad4 NFE exome

AF:

0.850

Gnomad4 OTH exome

AF:

0.837

GnomAD4 genome

AF:

0.841

AC:

127963

AN:

152128

Hom.:

53881

Cov.:

AF XY:

0.838

AC XY:

62286

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.856

Gnomad4 AMR

AF:

0.863

Gnomad4 ASJ

AF:

0.844

Gnomad4 EAS

AF:

0.817

Gnomad4 SAS

AF:

0.830

Gnomad4 FIN

AF:

0.735

Gnomad4 NFE

AF:

0.847

Gnomad4 OTH

AF:

0.848

Alfa

AF:

0.845

Hom.:

97736

Bravo

AF:

0.851

TwinsUK

AF:

0.856

AC:

3175

ALSPAC

AF:

0.855

AC:

3296

ESP6500AA

AF:

0.855

AC:

3768

ESP6500EA

AF:

0.851

AC:

7321

ExAC

AF:

0.831

AC:

100941

Asia WGS

AF:

0.838

AC:

2915

AN:

3478

EpiCase

AF:

0.845

EpiControl

AF:

0.842

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17000706) -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Pseudohypoaldosteronism type 2C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.8

DANN

Benign

0.12

DEOGEN2

Benign

0.061

T;.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.15

T;T;T;T;T

MetaRNN

Benign

7.2e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

.;.;N;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

2.7

N;.;N;.;N

REVEL

Benign

0.053

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.34

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.036

MPC

0.15

ClinPred

0.0012

GERP RS

0.64

Varity_R

0.045

gMVP

0.067

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over