chr17-42780745-C-T

Position:

chr17-42780745-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_032387.5(WNK4):c.47C>T(p.Thr16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,608,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

WNK4
NM_032387.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.19

Variant links:

Genes affected

WNK4 (HGNC:14544): (WNK lysine deficient protein kinase 4) This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

WNK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.077147454).

BP6

Variant 17-42780745-C-T is Benign according to our data. Variant chr17-42780745-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 323311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK4	NM_032387.5 linkuse as main transcript	c.47C>T	p.Thr16Ile	missense_variant	1/19	ENST00000246914.10	NP_115763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK4	ENST00000246914.10 linkuse as main transcript	c.47C>T	p.Thr16Ile	missense_variant	1/19	1	NM_032387.5	ENSP00000246914	P1	Q96J92-1
WNK4	ENST00000591448.5 linkuse as main transcript	c.47C>T	p.Thr16Ile	missense_variant, NMD_transcript_variant	1/18	1		ENSP00000467088

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000200

AC:

AN:

234600

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

129358

show subpopulations

Gnomad AFR exome

AF:

0.0000702

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000534

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000341

GnomAD4 exome

AF:

0.000350

AC:

510

AN:

1456582

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

235

AN XY:

724816

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000204

Gnomad4 NFE exome

AF:

0.000435

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000315

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000618

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000208

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2B

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 08, 2021	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.077

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.80

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.14

Sift

Uncertain

0.0030

Sift4G

Benign

0.10

Polyphen

0.0010

Vest4

0.13

MVP

0.49

MPC

0.70

ClinPred

0.037

GERP RS

2.3

Varity_R

0.18

gMVP

0.40

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