rs17755373

Positions:

chr12-890472-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000315939.11(WNK1):c.5468C>T(p.Pro1823Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,614,040 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 31)

Exomes 𝑓: 0.013 ( 234 hom. )

Consequence

WNK1
ENST00000315939.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.88

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 4.652 (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=0.0032887757).

BP6

Variant 12-890472-C-T is Benign according to our data. Variant chr12-890472-C-T is described in ClinVar as [Benign]. Clinvar id is 310836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-890472-C-T is described in Lovd as [Likely_benign]. Variant chr12-890472-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0106 (1617/152228) while in subpopulation SAS AF= 0.055 (265/4822). AF 95% confidence interval is 0.0495. There are 19 homozygotes in gnomad4. There are 889 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.6224C>T	p.Pro2075Leu	missense_variant	22/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 linkuse as main transcript	c.5468C>T	p.Pro1823Leu	missense_variant	22/28	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.6224C>T	p.Pro2075Leu	missense_variant	22/28	5	NM_213655.5	ENSP00000341292	A2	Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.5468C>T	p.Pro1823Leu	missense_variant	22/28	1	NM_018979.4	ENSP00000313059	P2	Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1620

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.00668

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.0549

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0165

AC:

4146

AN:

251436

Hom.:

AF XY:

0.0189

AC XY:

2567

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0329

Gnomad EAS exome

AF:

0.0221

Gnomad SAS exome

AF:

0.0486

Gnomad FIN exome

AF:

0.0151

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0132

AC:

19248

AN:

1461812

Hom.:

234

Cov.:

AF XY:

0.0145

AC XY:

10520

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.00534

Gnomad4 ASJ exome

AF:

0.0336

Gnomad4 EAS exome

AF:

0.0134

Gnomad4 SAS exome

AF:

0.0472

Gnomad4 FIN exome

AF:

0.0139

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0106

AC:

1617

AN:

152228

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

889

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.00667

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.0550

Gnomad4 FIN

AF:

0.0138

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00888

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0129

AC:

111

ExAC

AF:

0.0167

AC:

2031

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	WNK1: BP4, BS1, BS2 -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.13

T;.;D;.;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;.;M;.;.

MutationTaster

Benign

0.95

D;D;D;D;D

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.3

D;.;D;.;D

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;.;D;.;D

Sift4G

Uncertain

0.030

D;.;D;D;D

Polyphen

0.83

P;.;P;.;.

Vest4

0.40

MPC

0.12

ClinPred

0.051

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.11

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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