12-894671-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_213655.5(WNK1):c.6339+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,586,762 control chromosomes in the GnomAD database, including 47,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 4743 hom., cov: 32)

Exomes 𝑓: 0.24 ( 42519 hom. )

Consequence

WNK1
NM_213655.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.836

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

neuropathy, hereditary sensory and autonomic, type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
pseudohypoaldosteronism type 2C
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary sensory and autonomic neuropathy type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WNK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 12-894671-C-T is Benign according to our data. Variant chr12-894671-C-T is described in ClinVar as Benign. ClinVar VariationId is 674135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.6339+36C>T		intron_variant	Intron 23 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.5583+36C>T		intron_variant	Intron 23 of 27	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 link	c.6339+36C>T		intron_variant	Intron 23 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.5583+36C>T		intron_variant	Intron 23 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.248

AC:

37669

AN:

151916

Hom.:

4738

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.246

Gnomad OTH

AF:

0.265

GnomAD2 exomes

AF:

0.236

AC:

59206

AN:

251250

AF XY:

0.236

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.222

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.196

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.242

AC:

347147

AN:

1434730

Hom.:

42519

Cov.:

AF XY:

0.242

AC XY:

173385

AN XY:

715544

show subpopulations

African (AFR)

AF:

0.283

AC:

9300

AN:

32884

American (AMR)

AF:

0.222

AC:

9907

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7869

AN:

25950

East Asian (EAS)

AF:

0.213

AC:

8434

AN:

39510

South Asian (SAS)

AF:

0.241

AC:

20637

AN:

85670

European-Finnish (FIN)

AF:

0.195

AC:

10392

AN:

53330

Middle Eastern (MID)

AF:

0.319

AC:

1826

AN:

5716

European-Non Finnish (NFE)

AF:

0.243

AC:

264229

AN:

1087544

Other (OTH)

AF:

0.245

AC:

14553

AN:

59458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

12553

25106

37659

50212

62765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8976

17952

26928

35904

44880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.248

AC:

37703

AN:

152032

Hom.:

4743

Cov.:

AF XY:

0.245

AC XY:

18223

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.275

AC:

11385

AN:

41474

American (AMR)

AF:

0.231

AC:

3527

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1081

AN:

3466

East Asian (EAS)

AF:

0.196

AC:

1012

AN:

5174

South Asian (SAS)

AF:

0.254

AC:

1222

AN:

4818

European-Finnish (FIN)

AF:

0.187

AC:

1981

AN:

10574

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.246

AC:

16714

AN:

67936

Other (OTH)

AF:

0.270

AC:

570

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1444

2889

4333

5778

7222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.252

Hom.:

1156

Bravo

AF:

0.252

Asia WGS

AF:

0.255

AC:

885

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

8.1

(source)

DANN

Benign

0.63

PhyloP100

0.84

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over