rs72648621

chr12-827183-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_213655.5(WNK1):c.1074C>T(p.Thr358=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,178 control chromosomes in the GnomAD database, including 4 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 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: WNK1 NM_213655.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.205

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 12-827183-C-T is Benign according to our data. Variant chr12-827183-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289745.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr12-827183-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.205 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.1074C>T	p.Thr358=	synonymous_variant	3/28	ENST00000340908.9
WNK1	NM_018979.4	c.1074C>T	p.Thr358=	synonymous_variant	3/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.1074C>T	p.Thr358=	synonymous_variant	3/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.1074C>T	p.Thr358=	synonymous_variant	3/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00141 AC: 355 AN: 251428 Hom.: 2 AF XY: 0.00151 AC XY: 205 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00169 AC: 2466 AN: 1461892 Hom.: 4 Cov.: 32 AF XY: 0.00165 AC XY: 1197 AN XY: 727248

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74474

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.00212

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00213

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

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	May 12, 2021	- -
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 -

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

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	-0.44
Cadd	Benign	12
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs72648621; hg19: chr12-936349; COSMIC: COSV100269067; COSMIC: COSV100269067;