17-42780714-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032387.5(WNK4):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,608,676 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A6D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0093 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: WNK4 NM_032387.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0570

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021839142).
• BP6: Variant 17-42780714-G-A is Benign according to our data. Variant chr17-42780714-G-A is described in ClinVar as [Benign]. Clinvar id is 323310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00931 (1417/152252) while in subpopulation AFR AF= 0.0316 (1312/41552). AF 95% confidence interval is 0.0302. There are 21 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1414 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK4	NM_032387.5	c.16G>A	p.Ala6Thr	missense_variant	1/19	ENST00000246914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK4	ENST00000246914.10	c.16G>A	p.Ala6Thr	missense_variant	1/19	1	NM_032387.5	P1
WNK4	ENST00000591448.5	c.16G>A	p.Ala6Thr	missense_variant, NMD_transcript_variant	1/18	1

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152142 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00242 AC: 572 AN: 236368 Hom.: 8 AF XY: 0.00193 AC XY: 251 AN XY: 130046

Gnomad AFR exome AF: 0.0315

Gnomad AMR exome AF: 0.00236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00101 AC: 1473 AN: 1456424 Hom.: 27 Cov.: 31 AF XY: 0.000916 AC XY: 664 AN XY: 724718

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00931 AC: 1417 AN: 152252 Hom.: 21 Cov.: 32 AF XY: 0.00916 AC XY: 682 AN XY: 74436

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.000985 Hom.: 1

Bravo AF: 0.0100

ESP6500AA AF: 0.0245 AC: 107

ESP6500EA AF: 0.000470 AC: 4

ExAC AF: 0.00277 AC: 334

Asia WGS AF: 0.00145 AC: 5 AN: 3470

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

WNK4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 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
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	2.8
Dann	Benign	0.79
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.11
Sift	Benign	0.39	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.043
MVP		0.25
MPC		0.63
ClinPred		0.00047	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.16

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: rs61754324; hg19: chr17-40932732;