rs146042595

Positions:

chr12-908664-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_018979.4(WNK1):c.7021G>A(p.Gly2341Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,614,188 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00075 ( 2 hom. )

Consequence

WNK1
NM_018979.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.38

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 -8 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=0.025352627).

BP6

Variant 12-908664-G-A is Benign according to our data. Variant chr12-908664-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 306664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.7777G>A	p.Gly2593Ser	missense_variant	28/28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 linkuse as main transcript	c.7021G>A	p.Gly2341Ser	missense_variant	28/28	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.7777G>A	p.Gly2593Ser	missense_variant	28/28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.7021G>A	p.Gly2341Ser	missense_variant	28/28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000457

AC:

115

AN:

251448

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000712

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000753

AC:

1101

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000776

AC XY:

564

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000914

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000604

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000725

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	The WNK1 c.7801G>A; p.Gly2601Ser variant (rs146042595), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 306664). This variant is found in the general population with an overall allele frequency of 0.044% (125/282,838 alleles, including a single homozygote) in the Genome Aggregation Database. The glycine at codon 2601 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.053). Due to limited information, the clinical significance of the p.Gly2601Ser variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 10, 2022	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2021

The p.G2593S variant (also known as c.7777G>A), located in coding exon 28 of the WNK1 gene, results from a G to A substitution at nucleotide position 7777. The glycine at codon 2593 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Pseudohypoaldosteronism type 2C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.063

T;.;T;.;.

Eigen

Benign

-0.088

Eigen_PC

Benign

0.095

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.025

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.7

.;.;L;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

N;.;N;.;N

REVEL

Benign

0.053

Sift

Benign

0.28

T;.;T;.;T

Sift4G

Benign

1.0

T;.;T;T;T

Polyphen

0.17

B;.;B;.;.

Vest4

0.24

MVP

0.28

MPC

0.16

ClinPred

0.021

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.080

gMVP

0.49

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

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