17-42787442-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032387.5(WNK4):c.1641C>T(p.Ala547=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,842 control chromosomes in the GnomAD database, including 2,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (1231 hom., cov: 32)
  • Exomes 𝑓: 0.016 (1668 hom.)
• Consequence: WNK4 NM_032387.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.202

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-42787442-C-T is Benign according to our data. Variant chr17-42787442-C-T is described in ClinVar as [Benign]. Clinvar id is 323323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.202 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK4	NM_032387.5	c.1641C>T	p.Ala547=	synonymous_variant	7/19	ENST00000246914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK4	ENST00000246914.10	c.1641C>T	p.Ala547=	synonymous_variant	7/19	1	NM_032387.5	P1
WNK4	ENST00000591448.5	c.*142C>T		3_prime_UTR_variant, NMD_transcript_variant	6/18	1
WNK4	ENST00000587705.5	n.321C>T		non_coding_transcript_exon_variant	2/4	4
WNK4	ENST00000592072.1	n.321C>T		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11148 AN: 151876 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0547

GnomAD3 exomes AF: 0.0360 AC: 9040 AN: 251344 Hom.: 707 AF XY: 0.0351 AC XY: 4773 AN XY: 135846

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.00501

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0157 AC: 23011 AN: 1461848 Hom.: 1668 Cov.: 33 AF XY: 0.0176 AC XY: 12774 AN XY: 727220

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.0391

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.00525

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0737 AC: 11206 AN: 151994 Hom.: 1231 Cov.: 32 AF XY: 0.0734 AC XY: 5452 AN XY: 74304

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.0428

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.0541

Alfa AF: 0.0150 Hom.: 386

Bravo AF: 0.0799

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00219

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2017

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Pseudohypoaldosteronism type 2B 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.5
Dann	Benign	0.38

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

Other links and lift over

dbSNP: rs9916754; hg19: chr17-40939460; COSMIC: COSV55902593; COSMIC: COSV55902593;