rs1012729

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018979.4(WNK1):c.2328G>A(p.Gln776Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,613,584 control chromosomes in the GnomAD database, including 441,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37571 hom., cov: 30)

Exomes 𝑓: 0.74 ( 403847 hom. )

Consequence

WNK1
NM_018979.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.842

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-878316-G-A is Benign according to our data. Variant chr12-878316-G-A is described in ClinVar as [Benign]. Clinvar id is 261067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-878316-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.842 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.3822G>A	p.Gln1274Gln	synonymous_variant	12/28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.2328G>A	p.Gln776Gln	synonymous_variant	10/28	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 link	c.3822G>A	p.Gln1274Gln	synonymous_variant	12/28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.2328G>A	p.Gln776Gln	synonymous_variant	10/28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

105889

AN:

151722

Hom.:

37549

Cov.:

show subpopulations

Gnomad AFR

AF:

0.565

Gnomad AMI

AF:

0.867

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.808

Gnomad SAS

AF:

0.678

Gnomad FIN

AF:

0.812

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.744

Gnomad OTH

AF:

0.686

GnomAD3 exomes

AF:

0.739

AC:

185645

AN:

251352

Hom.:

69249

AF XY:

0.738

AC XY:

100312

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.558

Gnomad AMR exome

AF:

0.764

Gnomad ASJ exome

AF:

0.688

Gnomad EAS exome

AF:

0.803

Gnomad SAS exome

AF:

0.690

Gnomad FIN exome

AF:

0.804

Gnomad NFE exome

AF:

0.753

Gnomad OTH exome

AF:

0.713

GnomAD4 exome

AF:

0.742

AC:

1084659

AN:

1461748

Hom.:

403847

Cov.:

AF XY:

0.741

AC XY:

538598

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.560

Gnomad4 AMR exome

AF:

0.763

Gnomad4 ASJ exome

AF:

0.681

Gnomad4 EAS exome

AF:

0.789

Gnomad4 SAS exome

AF:

0.696

Gnomad4 FIN exome

AF:

0.804

Gnomad4 NFE exome

AF:

0.748

Gnomad4 OTH exome

AF:

0.730

GnomAD4 genome

AF:

0.698

AC:

105960

AN:

151836

Hom.:

37571

Cov.:

AF XY:

0.701

AC XY:

51999

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.565

Gnomad4 AMR

AF:

0.741

Gnomad4 ASJ

AF:

0.673

Gnomad4 EAS

AF:

0.808

Gnomad4 SAS

AF:

0.679

Gnomad4 FIN

AF:

0.812

Gnomad4 NFE

AF:

0.744

Gnomad4 OTH

AF:

0.681

Alfa

AF:

0.725

Hom.:

46232

Bravo

AF:

0.689

Asia WGS

AF:

0.703

AC:

2444

AN:

3478

EpiCase

AF:

0.722

EpiControl

AF:

0.730

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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+	-	- -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:2

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

not provided

Benign:2

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

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

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

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.53

DANN

Benign

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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