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.1287A>G(p.Ala429Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,613,654 control chromosomes in the GnomAD database, including 453,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A429A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.70 ( 38465 hom., cov: 31)

Exomes 𝑓: 0.75 ( 415104 hom. )

Consequence

WNK1
NM_213655.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.43

Publications

26 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=-0.9).

BP6

Variant 12-830136-A-G is Benign according to our data. Variant chr12-830136-A-G is described in ClinVar as Benign. ClinVar VariationId is 261066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 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.1287A>G	p.Ala429Ala	synonymous	Exon 4 of 28	NP_998820.3
WNK1	NM_018979.4	MANE Select	c.1287A>G	p.Ala429Ala	synonymous	Exon 4 of 28	NP_061852.3
WNK1	NM_001184985.2		c.1287A>G	p.Ala429Ala	synonymous	Exon 4 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.1287A>G	p.Ala429Ala	synonymous	Exon 4 of 28	ENSP00000341292.5
WNK1	ENST00000315939.11	TSL:1 MANE Select	c.1287A>G	p.Ala429Ala	synonymous	Exon 4 of 28	ENSP00000313059.6
WNK1	ENST00000530271.6	TSL:1	c.1287A>G	p.Ala429Ala	synonymous	Exon 4 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes

AF:

0.705

AC:

107067

AN:

151926

Hom.:

38443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.562

Gnomad AMI

AF:

0.868

Gnomad AMR

AF:

0.749

Gnomad ASJ

AF:

0.681

Gnomad EAS

AF:

0.875

Gnomad SAS

AF:

0.697

Gnomad FIN

AF:

0.813

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.752

Gnomad OTH

AF:

0.694

GnomAD2 exomes

AF:

0.750

AC:

188493

AN:

251420

AF XY:

0.750

show subpopulations

Gnomad AFR exome

AF:

0.553

Gnomad AMR exome

AF:

0.769

Gnomad ASJ exome

AF:

0.693

Gnomad EAS exome

AF:

0.867

Gnomad FIN exome

AF:

0.803

Gnomad NFE exome

AF:

0.760

Gnomad OTH exome

AF:

0.721

GnomAD4 exome

AF:

0.752

AC:

1099354

AN:

1461610

Hom.:

415104

Cov.:

AF XY:

0.751

AC XY:

546176

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.558

AC:

18695

AN:

33476

American (AMR)

AF:

0.768

AC:

34325

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.687

AC:

17954

AN:

26134

East Asian (EAS)

AF:

0.875

AC:

34750

AN:

39698

South Asian (SAS)

AF:

0.716

AC:

61744

AN:

86254

European-Finnish (FIN)

AF:

0.804

AC:

42953

AN:

53414

Middle Eastern (MID)

AF:

0.648

AC:

3740

AN:

5768

European-Non Finnish (NFE)

AF:

0.756

AC:

840519

AN:

1111766

Other (OTH)

AF:

0.740

AC:

44674

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15590

31180

46769

62359

77949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20324

40648

60972

81296

101620

<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:

0.705

AC:

107138

AN:

152044

Hom.:

38465

Cov.:

AF XY:

0.708

AC XY:

52609

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.563

AC:

23312

AN:

41438

American (AMR)

AF:

0.749

AC:

11444

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

2365

AN:

3472

East Asian (EAS)

AF:

0.875

AC:

4534

AN:

5184

South Asian (SAS)

AF:

0.698

AC:

3354

AN:

4808

European-Finnish (FIN)

AF:

0.813

AC:

8596

AN:

10578

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.752

AC:

51096

AN:

67980

Other (OTH)

AF:

0.690

AC:

1455

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1558

3116

4673

6231

7789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.724

Hom.:

62751

Bravo

AF:

0.696

Asia WGS

AF:

0.735

AC:

2556

AN:

3478

EpiCase

AF:

0.731

EpiControl

AF:

0.737

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

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

-0.90

CADD

Benign

0.46

(source)

DANN

Benign

0.48

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=77/23

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

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