12-862125-C-T

Position:

chr12-862125-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_213655.5(WNK1):c.1994C>T(p.Thr665Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0659 in 1,613,962 control chromosomes in the GnomAD database, including 3,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T665A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.056 ( 307 hom., cov: 32)

Exomes 𝑓: 0.067 ( 3546 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.03

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 4.7 (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=0.0026575327).

BP6

Variant 12-862125-C-T is Benign according to our data. Variant chr12-862125-C-T is described in ClinVar as [Benign]. Clinvar id is 137924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-862125-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.1994C>T	p.Thr665Ile	missense_variant	8/28	ENST00000340908.9
WNK1	NM_018979.4 linkuse as main transcript	c.1994C>T	p.Thr665Ile	missense_variant	8/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9 linkuse as main transcript	c.1994C>T	p.Thr665Ile	missense_variant	8/28	5	NM_213655.5	A2	Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.1994C>T	p.Thr665Ile	missense_variant	8/28	1	NM_018979.4	P2	Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.0557

AC:

8471

AN:

152050

Hom.:

308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0668

Gnomad ASJ

AF:

0.0861

Gnomad EAS

AF:

0.0845

Gnomad SAS

AF:

0.0301

Gnomad FIN

AF:

0.0811

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0636

GnomAD3 exomes

AF:

0.0661

AC:

16604

AN:

251344

Hom.:

652

AF XY:

0.0656

AC XY:

8905

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.0741

Gnomad ASJ exome

AF:

0.0826

Gnomad EAS exome

AF:

0.0928

Gnomad SAS exome

AF:

0.0255

Gnomad FIN exome

AF:

0.0865

Gnomad NFE exome

AF:

0.0717

Gnomad OTH exome

AF:

0.0820

GnomAD4 exome

AF:

0.0670

AC:

97886

AN:

1461794

Hom.:

3546

Cov.:

AF XY:

0.0665

AC XY:

48390

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.0750

Gnomad4 ASJ exome

AF:

0.0848

Gnomad4 EAS exome

AF:

0.0797

Gnomad4 SAS exome

AF:

0.0272

Gnomad4 FIN exome

AF:

0.0828

Gnomad4 NFE exome

AF:

0.0696

Gnomad4 OTH exome

AF:

0.0666

GnomAD4 genome

AF:

0.0556

AC:

8463

AN:

152168

Hom.:

307

Cov.:

AF XY:

0.0552

AC XY:

4107

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.0668

Gnomad4 ASJ

AF:

0.0861

Gnomad4 EAS

AF:

0.0845

Gnomad4 SAS

AF:

0.0295

Gnomad4 FIN

AF:

0.0811

Gnomad4 NFE

AF:

0.0732

Gnomad4 OTH

AF:

0.0629

Alfa

AF:

0.0729

Hom.:

1051

Bravo

AF:

0.0547

TwinsUK

AF:

0.0742

AC:

275

ALSPAC

AF:

0.0708

AC:

273

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0753

AC:

648

ExAC

AF:

0.0639

AC:

7756

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.0853

EpiControl

AF:

0.0812

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

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 29, 2023	- -

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 12, 2017

- -

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

Pathogenic

0.85

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;D;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D;D

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;M;M;M;M

MutationTaster

Benign

0.053

P;P;P;P;P

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

D;D;D;.;D

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;D;D;.;D

Sift4G

Uncertain

0.0050

D;.;T;D;D

Polyphen

0.34

B;.;B;.;.

Vest4

0.52

MPC

0.13

ClinPred

0.030

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.46

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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