rs61736907

chr12-896478-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_213655.5(WNK1):c.6747G>A(p.Glu2249=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,896 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (12 hom., cov: 29)
  • Exomes 𝑓: 0.00083 (22 hom.)
• Consequence: WNK1 NM_213655.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.164

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=-0.75).
• BP6: Variant 12-896478-G-A is Benign according to our data. Variant chr12-896478-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 306615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-896478-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.164 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00753 (1145/152002) while in subpopulation AFR AF= 0.0263 (1091/41430). AF 95% confidence interval is 0.025. There are 12 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.6747G>A	p.Glu2249=	synonymous_variant	24/28	ENST00000340908.9
WNK1	NM_018979.4	c.5991G>A	p.Glu1997=	synonymous_variant	24/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.6747G>A	p.Glu2249=	synonymous_variant	24/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.5991G>A	p.Glu1997=	synonymous_variant	24/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.00751 AC: 1140 AN: 151884 Hom.: 12 Cov.: 29

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00203 AC: 511 AN: 251250 Hom.: 7 AF XY: 0.00149 AC XY: 202 AN XY: 135782

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000828 AC: 1211 AN: 1461894 Hom.: 22 Cov.: 31 AF XY: 0.000718 AC XY: 522 AN XY: 727248

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00753 AC: 1145 AN: 152002 Hom.: 12 Cov.: 29 AF XY: 0.00707 AC XY: 525 AN XY: 74298

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00348 Hom.: 2

Bravo AF: 0.00826

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	- -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	3.1
Dann	Benign	0.83

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: rs61736907; hg19: chr12-1005644; COSMIC: COSV104411223; COSMIC: COSV104411223;