Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_213655.5(WNK1):c.258T>C(p.Cys86Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,612,660 control chromosomes in the GnomAD database, including 799,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72777 hom., cov: 33)

Exomes 𝑓: 1.0 ( 726897 hom. )

Consequence

WNK1
NM_213655.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.839

Publications

18 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 12-753823-T-C is Benign according to our data. Variant chr12-753823-T-C is described in ClinVar as Benign. ClinVar VariationId is 261069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.839 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WNK1	NM_213655.5	MANE Plus Clinical	c.258T>C	p.Cys86Cys	synonymous	Exon 1 of 28	NP_998820.3
WNK1	NM_018979.4	MANE Select	c.258T>C	p.Cys86Cys	synonymous	Exon 1 of 28	NP_061852.3
WNK1	NM_001184985.2		c.258T>C	p.Cys86Cys	synonymous	Exon 1 of 28	NP_001171914.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.258T>C	p.Cys86Cys	synonymous	Exon 1 of 28	ENSP00000341292.5
WNK1	ENST00000315939.11	TSL:1 MANE Select	c.258T>C	p.Cys86Cys	synonymous	Exon 1 of 28	ENSP00000313059.6
WNK1	ENST00000530271.6	TSL:1	c.258T>C	p.Cys86Cys	synonymous	Exon 1 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes

AF:

0.977

AC:

148670

AN:

152196

Hom.:

72717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.919

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.992

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.984

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.987

GnomAD2 exomes

AF:

0.994

AC:

242546

AN:

243996

AF XY:

0.996

show subpopulations

Gnomad AFR exome

AF:

0.916

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.998

AC:

1456933

AN:

1460346

Hom.:

726897

Cov.:

110

AF XY:

0.998

AC XY:

725045

AN XY:

726492

show subpopulations

African (AFR)

AF:

0.912

AC:

30544

AN:

33476

American (AMR)

AF:

0.997

AC:

44583

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26126

AN:

26126

East Asian (EAS)

AF:

1.00

AC:

39684

AN:

39694

South Asian (SAS)

AF:

1.00

AC:

86242

AN:

86258

European-Finnish (FIN)

AF:

1.00

AC:

51986

AN:

51986

Middle Eastern (MID)

AF:

0.998

AC:

5759

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111878

AN:

1111940

Other (OTH)

AF:

0.996

AC:

60131

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

246

492

738

984

1230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.977

AC:

148790

AN:

152314

Hom.:

72777

Cov.:

AF XY:

0.978

AC XY:

72831

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.919

AC:

38191

AN:

41560

American (AMR)

AF:

0.993

AC:

15193

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5164

AN:

5164

South Asian (SAS)

AF:

0.999

AC:

4827

AN:

4830

European-Finnish (FIN)

AF:

1.00

AC:

10630

AN:

10630

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68025

AN:

68030

Other (OTH)

AF:

0.987

AC:

2088

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

168

335

503

670

838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.989

Hom.:

54212

Bravo

AF:

0.974

Asia WGS

AF:

0.996

AC:

3465

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Neuropathy, hereditary sensory and autonomic, type 2A (2)

not provided (2)

Pseudohypoaldosteronism type 2C (1)

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over