chr12-896637-T-C

Position:

chr12-896637-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.754

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr12-896637-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.754 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.6906T>C	p.Leu2302=	synonymous_variant	24/28	ENST00000340908.9
WNK1	NM_018979.4 linkuse as main transcript	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 linkuse as main transcript	c.6906T>C	p.Leu2302=	synonymous_variant	24/28	5	NM_213655.5	A2	Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.6150T>C	p.Leu2050=	synonymous_variant	24/28	1	NM_018979.4	P2	Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

247

AN:

150326

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00139

AC XY:

187

AN XY:

134454

show subpopulations

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.:

Cov.:

AF XY:

0.00160

AC XY:

1159

AN XY:

725030

show subpopulations

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.:

Cov.:

AF XY:

0.00147

AC XY:

108

AN XY:

73380

show subpopulations

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.:

Bravo

AF:

0.00197

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

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

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over