rs79816263

chr12-879689-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_018979.4(WNK1):c.2490G>A(p.Pro830=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,440 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 29)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.29

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-879689-G-A is Benign according to our data. Variant chr12-879689-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 284012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-879689-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.29 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.2490G>A	p.Pro830=	synonymous_variant	11/28	ENST00000315939.11
WNK1	NM_213655.5	c.3867+1328G>A		intron_variant		ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.2490G>A	p.Pro830=	synonymous_variant	11/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.3867+1328G>A		intron_variant		5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 323 AN: 151492 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00894

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.00179 AC: 449 AN: 251442 Hom.: 3 AF XY: 0.00184 AC XY: 250 AN XY: 135894

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00212 AC: 3100 AN: 1461832 Hom.: 7 Cov.: 35 AF XY: 0.00209 AC XY: 1519 AN XY: 727210

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00213 AC: 323 AN: 151608 Hom.: 4 Cov.: 29 AF XY: 0.00243 AC XY: 180 AN XY: 74082

Gnomad4 AFR AF: 0.000653

Gnomad4 AMR AF: 0.00893

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.00217

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00241

EpiCase AF: 0.00196

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	WNK1: BP4, BP7 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 21, 2015

- -

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 18, 2024

- -

WNK1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2023

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs79816263; hg19: chr12-988855; COSMIC: COSV100267110; COSMIC: COSV100267110;