Genetic Variant NM_213655.5:c.3822G>A (chr12-878316-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_213655.5(WNK1):c.3822G>A(p.Gln1274Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,613,584 control chromosomes in the GnomAD database, including 441,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37571 hom., cov: 30)

Exomes 𝑓: 0.74 ( 403847 hom. )

Consequence

WNK1
NM_213655.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.842

Publications

32 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.121).

BP6

Variant 12-878316-G-A is Benign according to our data. Variant chr12-878316-G-A is described in ClinVar as Benign. ClinVar VariationId is 261067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.842 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 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.3822G>A	p.Gln1274Gln	synonymous	Exon 12 of 28	NP_998820.3
WNK1	NM_018979.4	MANE Select	c.2328G>A	p.Gln776Gln	synonymous	Exon 10 of 28	NP_061852.3
WNK1	NM_001184985.2		c.3567G>A	p.Gln1189Gln	synonymous	Exon 11 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.3822G>A	p.Gln1274Gln	synonymous	Exon 12 of 28	ENSP00000341292.5
WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2328G>A	p.Gln776Gln	synonymous	Exon 10 of 28	ENSP00000313059.6
WNK1	ENST00000530271.6	TSL:1	c.3567G>A	p.Gln1189Gln	synonymous	Exon 11 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

105889

AN:

151722

Hom.:

37549

Cov.:

show subpopulations

Gnomad AFR

AF:

0.565

Gnomad AMI

AF:

0.867

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.808

Gnomad SAS

AF:

0.678

Gnomad FIN

AF:

0.812

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.744

Gnomad OTH

AF:

0.686

GnomAD2 exomes

AF:

0.739

AC:

185645

AN:

251352

AF XY:

0.738

show subpopulations

Gnomad AFR exome

AF:

0.558

Gnomad AMR exome

AF:

0.764

Gnomad ASJ exome

AF:

0.688

Gnomad EAS exome

AF:

0.803

Gnomad FIN exome

AF:

0.804

Gnomad NFE exome

AF:

0.753

Gnomad OTH exome

AF:

0.713

GnomAD4 exome

AF:

0.742

AC:

1084659

AN:

1461748

Hom.:

403847

Cov.:

AF XY:

0.741

AC XY:

538598

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.560

AC:

18742

AN:

33472

American (AMR)

AF:

0.763

AC:

34127

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

17787

AN:

26130

East Asian (EAS)

AF:

0.789

AC:

31313

AN:

39692

South Asian (SAS)

AF:

0.696

AC:

60048

AN:

86254

European-Finnish (FIN)

AF:

0.804

AC:

42973

AN:

53418

Middle Eastern (MID)

AF:

0.637

AC:

3676

AN:

5768

European-Non Finnish (NFE)

AF:

0.748

AC:

831929

AN:

1111900

Other (OTH)

AF:

0.730

AC:

44064

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

16581

33162

49744

66325

82906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20240

40480

60720

80960

101200

<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:

0.698

AC:

105960

AN:

151836

Hom.:

37571

Cov.:

AF XY:

0.701

AC XY:

51999

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.565

AC:

23353

AN:

41322

American (AMR)

AF:

0.741

AC:

11321

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.673

AC:

2333

AN:

3466

East Asian (EAS)

AF:

0.808

AC:

4182

AN:

5176

South Asian (SAS)

AF:

0.679

AC:

3266

AN:

4810

European-Finnish (FIN)

AF:

0.812

AC:

8547

AN:

10524

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.744

AC:

50547

AN:

67958

Other (OTH)

AF:

0.681

AC:

1435

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1549

3098

4647

6196

7745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.720

Hom.:

57675

Bravo

AF:

0.689

Asia WGS

AF:

0.703

AC:

2444

AN:

3478

EpiCase

AF:

0.722

EpiControl

AF:

0.730

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neuropathy, hereditary sensory and autonomic, type 2A

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Pseudohypoaldosteronism type 2C

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.53

(source)

DANN

Benign

0.33

PhyloP100

-0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over