rs34032084

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_213655.5(WNK1):c.4245+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,583,204 control chromosomes in the GnomAD database, including 14,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 938 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13642 hom. )

Consequence

WNK1
NM_213655.5 splice_donor_region, intron

Scores

Splicing: ADA: 0.0001857

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.228

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 12-883063-C-T is Benign according to our data. Variant chr12-883063-C-T is described in ClinVar as [Benign]. Clinvar id is 261071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-883063-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4 linkuse as main transcript	c.3489+4C>T		splice_donor_region_variant, intron_variant		ENST00000315939.11
WNK1	NM_213655.5 linkuse as main transcript	c.4245+4C>T		splice_donor_region_variant, intron_variant		ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11 linkuse as main transcript	c.3489+4C>T		splice_donor_region_variant, intron_variant		1	NM_018979.4	P2	Q9H4A3-1
WNK1	ENST00000340908.9 linkuse as main transcript	c.4245+4C>T		splice_donor_region_variant, intron_variant		5	NM_213655.5	A2	Q9H4A3-5

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15600

AN:

152070

Hom.:

939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0444

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0881

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.0945

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.0971

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.116

GnomAD3 exomes

AF:

0.116

AC:

29237

AN:

251360

Hom.:

1967

AF XY:

0.123

AC XY:

16729

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0447

Gnomad AMR exome

AF:

0.0573

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.0835

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.0914

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.135

AC:

192763

AN:

1431016

Hom.:

13642

Cov.:

AF XY:

0.136

AC XY:

97430

AN XY:

714218

show subpopulations

Gnomad4 AFR exome

AF:

0.0441

Gnomad4 AMR exome

AF:

0.0612

Gnomad4 ASJ exome

AF:

0.115

Gnomad4 EAS exome

AF:

0.113

Gnomad4 SAS exome

AF:

0.173

Gnomad4 FIN exome

AF:

0.0974

Gnomad4 NFE exome

AF:

0.141

Gnomad4 OTH exome

AF:

0.127

GnomAD4 genome

AF:

0.102

AC:

15599

AN:

152188

Hom.:

938

Cov.:

AF XY:

0.101

AC XY:

7527

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0444

Gnomad4 AMR

AF:

0.0880

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.0940

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.0971

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.122

Hom.:

668

Bravo

AF:

0.0982

Asia WGS

AF:

0.125

AC:

435

AN:

3476

EpiCase

AF:

0.138

EpiControl

AF:

0.143

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, 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	-	- -

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

Athena Diagnostics

Jun 09, 2017

- -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.016

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