rs9804992

chr12-879728-G-Achr12-879728-G-T

Variant summary

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

The NM_018979.4(WNK1):c.2529G>A(p.Gln843=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,464 control chromosomes in the GnomAD database, including 20,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1636 hom., cov: 29)
  • Exomes 𝑓: 0.16 (18769 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.160

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-879728-G-A is Benign according to our data. Variant chr12-879728-G-A is described in ClinVar as [Benign]. Clinvar id is 261068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-879728-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.2529G>A	p.Gln843=	synonymous_variant	11/28	ENST00000315939.11
WNK1	NM_213655.5	c.3867+1367G>A		intron_variant		ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.2529G>A	p.Gln843=	synonymous_variant	11/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.3867+1367G>A		intron_variant		5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22182 AN: 151540 Hom.: 1633 Cov.: 29

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0937

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.157 AC: 39484 AN: 251472 Hom.: 3286 AF XY: 0.158 AC XY: 21482 AN XY: 135914

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0831

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.158 AC: 231110 AN: 1461806 Hom.: 18769 Cov.: 37 AF XY: 0.159 AC XY: 115557 AN XY: 727214

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.146 AC: 22206 AN: 151658 Hom.: 1636 Cov.: 29 AF XY: 0.145 AC XY: 10746 AN XY: 74094

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.0932

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.151

Alfa AF: 0.156 Hom.: 3221

Bravo AF: 0.151

Asia WGS AF: 0.141 AC: 492 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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. -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.40
Dann	Benign	0.75

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: rs9804992; hg19: chr12-988894; COSMIC: COSV60025012; COSMIC: COSV60025012;