rs151331381

chr12-896637-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_213655.5(WNK1):c.6906T>C(p.Leu2302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,608,302 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: WNK1 NM_213655.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.754

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-896637-T-C is Benign according to our data. Variant chr12-896637-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289744.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr12-896637-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.754 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.6906T>C	p.Leu2302=	synonymous_variant	24/28	ENST00000340908.9
WNK1	NM_018979.4	c.6150T>C	p.Leu2050=	synonymous_variant	24/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.6906T>C	p.Leu2302=	synonymous_variant	24/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.6150T>C	p.Leu2050=	synonymous_variant	24/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 247 AN: 150326 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000863

Gnomad FIN AF: 0.0000962

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00342

GnomAD3 exomes AF: 0.00134 AC: 333 AN: 248420 Hom.: 1 AF XY: 0.00139 AC XY: 187 AN XY: 134454

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000305

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000364

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00165 AC: 2404 AN: 1457858 Hom.: 3 Cov.: 31 AF XY: 0.00160 AC XY: 1159 AN XY: 725030

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.000462

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000408

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00164 AC: 246 AN: 150444 Hom.: 0 Cov.: 28 AF XY: 0.00147 AC XY: 108 AN XY: 73380

Gnomad4 AFR AF: 0.000367

Gnomad4 AMR AF: 0.00293

Gnomad4 ASJ AF: 0.000579

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000864

Gnomad4 FIN AF: 0.0000962

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00338

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.00197

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	WNK1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2020	- -

Pseudohypoaldosteronism type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	8.1
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs151331381; hg19: chr12-1005803;