rs12828016

Positions:

chr12-889199-G-T

Variant summary

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

The NM_018979.4(WNK1):c.5424G>T(p.Met1808Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,612,936 control chromosomes in the GnomAD database, including 123,394 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 0.41 ( 13066 hom., cov: 32)

Exomes 𝑓: 0.39 ( 110328 hom. )

Consequence

WNK1
NM_018979.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.446

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:

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=2.491094E-5).

BP6

Variant 12-889199-G-T is Benign according to our data. Variant chr12-889199-G-T is described in ClinVar as [Benign]. Clinvar id is 261073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-889199-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.499 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.6180G>T	p.Met2060Ile	missense_variant	21/28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 linkuse as main transcript	c.5424G>T	p.Met1808Ile	missense_variant	21/28	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.6180G>T	p.Met2060Ile	missense_variant	21/28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.5424G>T	p.Met1808Ile	missense_variant	21/28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.407

AC:

61765

AN:

151874

Hom.:

13054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.505

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.286

Gnomad SAS

AF:

0.462

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.429

GnomAD3 exomes

AF:

0.370

AC:

92947

AN:

251292

Hom.:

18022

AF XY:

0.375

AC XY:

50881

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.513

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.279

Gnomad SAS exome

AF:

0.452

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.398

GnomAD4 exome

AF:

0.386

AC:

563448

AN:

1460944

Hom.:

110328

Cov.:

AF XY:

0.388

AC XY:

281819

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.511

Gnomad4 AMR exome

AF:

0.294

Gnomad4 ASJ exome

AF:

0.409

Gnomad4 EAS exome

AF:

0.323

Gnomad4 SAS exome

AF:

0.446

Gnomad4 FIN exome

AF:

0.290

Gnomad4 NFE exome

AF:

0.386

Gnomad4 OTH exome

AF:

0.390

GnomAD4 genome

AF:

0.407

AC:

61814

AN:

151992

Hom.:

13066

Cov.:

AF XY:

0.401

AC XY:

29825

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.505

Gnomad4 AMR

AF:

0.341

Gnomad4 ASJ

AF:

0.414

Gnomad4 EAS

AF:

0.286

Gnomad4 SAS

AF:

0.461

Gnomad4 FIN

AF:

0.283

Gnomad4 NFE

AF:

0.387

Gnomad4 OTH

AF:

0.432

Alfa

AF:

0.394

Hom.:

31581

Bravo

AF:

0.412

TwinsUK

AF:

0.394

AC:

1462

ALSPAC

AF:

0.384

AC:

1480

ESP6500AA

AF:

0.510

AC:

2248

ESP6500EA

AF:

0.391

AC:

3363

ExAC

AF:

0.377

AC:

45722

Asia WGS

AF:

0.412

AC:

1433

AN:

3478

EpiCase

AF:

0.408

EpiControl

AF:

0.404

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:2

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

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pseudohypoaldosteronism type 2C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

0.11

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.060

T;.;T;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.077

T;T;T;T;T

MetaRNN

Benign

0.000025

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.69

.;.;N;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

0.19

N;.;N;.;N

REVEL

Benign

0.011

Sift

Benign

0.21

T;.;T;.;T

Sift4G

Benign

0.43

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.086

MutPred

0.28

.;.;Loss of catalytic residue at M1808 (P = 0.0215);.;.;

MPC

0.13

ClinPred

0.0011

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.19

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

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