Genetic Variant WNK1:c.3718-2613G>T (chr12-875599-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_213655.5(WNK1):c.3718-2613G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,906 control chromosomes in the GnomAD database, including 11,673 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 0.38 ( 11673 hom., cov: 32)

Consequence

WNK1
NM_213655.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.559

Publications

2 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.3718-2613G>T		intron_variant	Intron 11 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.2224-2613G>T		intron_variant	Intron 9 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.3718-2613G>T		intron_variant	Intron 11 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.2224-2613G>T		intron_variant	Intron 9 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58390

AN:

151788

Hom.:

11665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.496

Gnomad AMR

AF:

0.407

Gnomad ASJ

AF:

0.369

Gnomad EAS

AF:

0.523

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.431

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.433

Gnomad OTH

AF:

0.372

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

GnomAD4 genome

AF:

0.385

AC:

58417

AN:

151906

Hom.:

11673

Cov.:

AF XY:

0.385

AC XY:

28612

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.276

AC:

11429

AN:

41404

American (AMR)

AF:

0.407

AC:

6224

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

1278

AN:

3468

East Asian (EAS)

AF:

0.523

AC:

2711

AN:

5182

South Asian (SAS)

AF:

0.320

AC:

1537

AN:

4810

European-Finnish (FIN)

AF:

0.431

AC:

4531

AN:

10518

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.433

AC:

29401

AN:

67928

Other (OTH)

AF:

0.370

AC:

780

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1847

3695

5542

7390

9237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.405

Hom.:

1669

Bravo

AF:

0.381

Asia WGS

AF:

0.393

AC:

1363

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.33

(source)

DANN

Benign

0.20

PhyloP100

-0.56

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over