rs11554421

Positions:

chr12-753986-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 4.7 (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=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 id is 137927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-753986-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.421G>A	p.Ala141Thr	missense_variant	1/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 linkuse as main transcript	c.421G>A	p.Ala141Thr	missense_variant	1/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 linkuse as main transcript	c.421G>A	p.Ala141Thr	missense_variant	1/28	5	NM_213655.5	ENSP00000341292	A2	Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.421G>A	p.Ala141Thr	missense_variant	1/28	1	NM_018979.4	ENSP00000313059	P2	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

GnomAD3 exomes

AF:

0.123

AC:

24434

AN:

199102

Hom.:

1819

AF XY:

0.130

AC XY:

14143

AN XY:

109112

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 SAS exome

AF:

0.159

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

Gnomad4 AFR exome

AF:

0.0264

Gnomad4 AMR exome

AF:

0.0549

Gnomad4 ASJ exome

AF:

0.114

Gnomad4 EAS exome

AF:

0.0475

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.230

Gnomad4 NFE exome

AF:

0.123

Gnomad4 OTH exome

AF:

0.122

GnomAD4 genome

AF:

0.0986

AC:

15015

AN:

152250

Hom.:

970

Cov.:

AF XY:

0.104

AC XY:

7727

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0304

Gnomad4 AMR

AF:

0.0724

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.0586

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.123

Gnomad4 OTH

AF:

0.0879

Alfa

AF:

0.110

Hom.:

593

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2018	- -

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. -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

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;.

MutationTaster

Benign

1.0

P;P;P;P;P

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

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