dbSNP rs953361: WNK1:c.6266-1921G>A (chr12-892641-G-A) – 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.6266-1921G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 151,958 control chromosomes in the GnomAD database, including 10,452 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 0.36 ( 10452 hom., cov: 31)

Consequence

WNK1
NM_213655.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.270

Publications

7 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=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.6266-1921G>A		intron_variant	Intron 22 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4 link	c.5510-1921G>A		intron_variant	Intron 22 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.6266-1921G>A		intron_variant	Intron 22 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11 link	c.5510-1921G>A		intron_variant	Intron 22 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

54941

AN:

151840

Hom.:

10443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.402

Gnomad AMR

AF:

0.460

Gnomad ASJ

AF:

0.315

Gnomad EAS

AF:

0.525

Gnomad SAS

AF:

0.330

Gnomad FIN

AF:

0.373

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.392

Gnomad OTH

AF:

0.333

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

GnomAD4 genome

AF:

0.362

AC:

54975

AN:

151958

Hom.:

10452

Cov.:

AF XY:

0.363

AC XY:

26972

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.261

AC:

10807

AN:

41412

American (AMR)

AF:

0.461

AC:

7037

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

1094

AN:

3468

East Asian (EAS)

AF:

0.525

AC:

2707

AN:

5158

South Asian (SAS)

AF:

0.329

AC:

1588

AN:

4824

European-Finnish (FIN)

AF:

0.373

AC:

3938

AN:

10558

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.392

AC:

26661

AN:

67944

Other (OTH)

AF:

0.332

AC:

701

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1742

3484

5225

6967

8709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<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:

0.360

Hom.:

1539

Bravo

AF:

0.366

Asia WGS

AF:

0.399

AC:

1385

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.49

(source)

DANN

Benign

0.63

PhyloP100

-0.27

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