rs149852592

chr12-885787-T-C

Variant summary

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

The NM_213655.5(WNK1):c.5739T>C(p.Ser1913=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,214 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (16 hom.)
• Consequence: WNK1 NM_213655.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.925

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=-0.53).
• BP6: Variant 12-885787-T-C is Benign according to our data. Variant chr12-885787-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 310832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-885787-T-C is described in Lovd as [Benign]. Variant chr12-885787-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.925 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.5739T>C	p.Ser1913=	synonymous_variant	19/28	ENST00000340908.9
WNK1	NM_018979.4	c.4983T>C	p.Ser1661=	synonymous_variant	19/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.5739T>C	p.Ser1913=	synonymous_variant	19/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.4983T>C	p.Ser1661=	synonymous_variant	19/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00224 AC: 564 AN: 251396 Hom.: 6 AF XY: 0.00263 AC XY: 358 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00820

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00132 AC: 1927 AN: 1461892 Hom.: 16 Cov.: 36 AF XY: 0.00161 AC XY: 1171 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00829

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000700

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74484

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.000740

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	WNK1: BP4, BP7, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	8.4
Dann	Benign	0.65

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: rs149852592; hg19: chr12-994953;