Genetic Variant WNK1:c.759+26412T>G (chr12-780736-T-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_213655.5(WNK1):c.759+26412T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,192 control chromosomes in the GnomAD database, including 3,969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 3969 hom., cov: 33)

Consequence

WNK1
NM_213655.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.02

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.759+26412T>G		intron_variant	Intron 1 of 27	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.759+26412T>G		intron_variant	Intron 1 of 27	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 link	c.759+26412T>G		intron_variant	Intron 1 of 27	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.759+26412T>G		intron_variant	Intron 1 of 27	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33680

AN:

152074

Hom.:

3963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.287

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.316

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.221

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.221

AC:

33700

AN:

152192

Hom.:

3969

Cov.:

AF XY:

0.223

AC XY:

16613

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.154

AC:

6400

AN:

41522

American (AMR)

AF:

0.288

AC:

4397

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

667

AN:

3472

East Asian (EAS)

AF:

0.316

AC:

1638

AN:

5180

South Asian (SAS)

AF:

0.217

AC:

1050

AN:

4830

European-Finnish (FIN)

AF:

0.216

AC:

2291

AN:

10588

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.244

AC:

16573

AN:

68002

Other (OTH)

AF:

0.220

AC:

465

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1344

2688

4032

5376

6720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.238

Hom.:

19930

Bravo

AF:

0.226

Asia WGS

AF:

0.237

AC:

824

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

3.0

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over