rs72647372

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_213655.5(WNK1):c.578C>A(p.Pro193Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,612,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00055 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.601

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011934072).

BP6

Variant 12-754143-C-A is Benign according to our data. Variant chr12-754143-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310545.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00115 (1681/1460426) while in subpopulation NFE AF = 0.00143 (1594/1111996). AF 95% confidence interval is 0.00137. There are 1 homozygotes in GnomAdExome4. There are 795 alleles in the male GnomAdExome4 subpopulation. Median coverage is 94. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.578C>A	p.Pro193Gln	missense_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.578C>A	p.Pro193Gln	missense_variant	Exon 1 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 link	c.578C>A	p.Pro193Gln	missense_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.578C>A	p.Pro193Gln	missense_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000489

AC:

121

AN:

247518

AF XY:

0.000490

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.000776

Gnomad OTH exome

AF:

0.000988

GnomAD4 exome

AF:

0.00115

AC:

1681

AN:

1460426

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

795

AN XY:

726484

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000514

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000384

AC:

AN:

52100

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00143

AC:

1594

AN:

1111996

Other (OTH)

AF:

0.000696

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

114

229

343

458

572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.000551

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41594

American (AMR)

AF:

0.000327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000823

AC:

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000744

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000470

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WNK1: PM2:Supporting, BP4

Feb 01, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Nov 29, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The WNK1 c.578C>A; p.Pro193Gln variant (rs72647372), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 310545). This variant is found in the general population with an overall allele frequency of 0.050% (139/278908 alleles) in the Genome Aggregation Database. The proline at codon 193 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro193Gln variant is uncertain at this time.

Inborn genetic diseases

Uncertain:1

Mar 09, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P193Q variant (also known as c.578C>A), located in coding exon 1 of the WNK1 gene, results from a C to A substitution at nucleotide position 578. The proline at codon 193 is replaced by glutamine, an amino acid with similar properties. This amino acid position is not well conserved in available 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

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.096

T;.;T;.;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.78

T;T;T;T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

.;L;L;L;L;.

PhyloP100

0.60

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

N;D;N;.;D;D

REVEL

Benign

0.15

Sift

Benign

0.23

T;T;T;.;T;T

Sift4G

Benign

0.63

T;.;T;T;T;T

Vest4

0.090

ClinPred

0.020

GERP RS

3.4

Varity_R

0.098

gMVP

0.19

Mutation Taster

=91/9

polymorphism

(source)

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

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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