rs9804992

Variant names:

• chr12-879728-G-A
• rs9804992
• NM_018979.4:c.2529G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-879728-G-A
• chr12-879728-G-C
• chr12-879728-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018979.4(WNK1):​c.2529G>A​(p.Gln843Gln) 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:5
• Conservation: PhyloP100: -0.160
• Publications: 25 publications found

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]

WNK1 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• pseudohypoaldosteronism type 2C

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
WNK1	NM_018979.4	c.2529G>A	p.Gln843Gln	synonymous_variant	Exon 11 of 28	ENST00000315939.11	NP_061852.3
WNK1	NM_213655.5	c.3867+1367G>A		intron_variant	Intron 12 of 27	ENST00000340908.9	NP_998820.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000315939.11	c.2529G>A	p.Gln843Gln	synonymous_variant	Exon 11 of 28	1	NM_018979.4	ENSP00000313059.6
WNK1	ENST00000340908.9	c.3867+1367G>A		intron_variant	Intron 12 of 27	5	NM_213655.5	ENSP00000341292.5

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

GnomAD2 exomes AF: 0.157 AC: 39484 AN: 251472 AF XY: 0.158

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 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

African (AFR) AF: 0.132 AC: 4431 AN: 33480

American (AMR) AF: 0.211 AC: 9428 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3759 AN: 26134

East Asian (EAS) AF: 0.113 AC: 4503 AN: 39698

South Asian (SAS) AF: 0.194 AC: 16761 AN: 86256

European-Finnish (FIN) AF: 0.112 AC: 6001 AN: 53414

Middle Eastern (MID) AF: 0.174 AC: 1002 AN: 5768

European-Non Finnish (NFE) AF: 0.158 AC: 175887 AN: 1111942

Other (OTH) AF: 0.155 AC: 9338 AN: 60392

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

African (AFR) AF: 0.127 AC: 5249 AN: 41328

American (AMR) AF: 0.194 AC: 2952 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3464

East Asian (EAS) AF: 0.0932 AC: 480 AN: 5152

South Asian (SAS) AF: 0.182 AC: 873 AN: 4788

European-Finnish (FIN) AF: 0.111 AC: 1170 AN: 10504

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10487 AN: 67892

Other (OTH) AF: 0.151 AC: 317 AN: 2094

Alfa AF: 0.155 Hom.: 3879

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism type 2C Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.40
DANN	Benign	0.75
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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