rs72650732

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_SupportingBP6_Very_StrongBS2

The NM_213655.5(WNK1):c.5361_5363del(p.Ser1788del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,742 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 7 hom. )

Consequence

WNK1
NM_213655.5 inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.96

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 -11 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_213655.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 12-885406-TAGC-T is Benign according to our data. Variant chr12-885406-TAGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 310831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-885406-TAGC-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_018979.4 linkuse as main transcript	c.4605_4607del	p.Ser1536del	inframe_deletion	19/28	ENST00000315939.11	NP_061852.3
WNK1	NM_213655.5 linkuse as main transcript	c.5361_5363del	p.Ser1788del	inframe_deletion	19/28	ENST00000340908.9	NP_998820.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000315939.11 linkuse as main transcript	c.4605_4607del	p.Ser1536del	inframe_deletion	19/28	1	NM_018979.4	ENSP00000313059	P2	Q9H4A3-1
WNK1	ENST00000340908.9 linkuse as main transcript	c.5361_5363del	p.Ser1788del	inframe_deletion	19/28	5	NM_213655.5	ENSP00000341292	A2	Q9H4A3-5

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

224

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00226

AC:

568

AN:

250998

Hom.:

AF XY:

0.00206

AC XY:

279

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00569

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00136

AC:

1988

AN:

1461426

Hom.:

AF XY:

0.00139

AC XY:

1012

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00552

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00160

Gnomad4 FIN exome

AF:

0.00759

Gnomad4 NFE exome

AF:

0.000972

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152316

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00753

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000387

Hom.:

Bravo

AF:

0.00129

EpiCase

AF:

0.00120

EpiControl

AF:

0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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	Mar 01, 2024	WNK1: PM4:Supporting, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 23, 2024

Variant summary: WNK1 c.4605_4607delCAG (p.Ser1536del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0023 in 250998 control chromosomes, predominantly at a frequency of 0.0057 within the Latino subpopulation in the gnomAD database, including 3 homozygotes. To our knowledge, no occurrence of c.4605_4607delCAG in individuals affected with Neuropathy, Hereditary Sensory And Autonomic, Type 2A and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 310831). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary sensory and autonomic neuropathy type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Pseudohypoaldosteronism type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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