12-753114-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018979.4(WNK1):c.-452G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 153,078 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 210 hom., cov: 31)

Exomes 𝑓: 0.048 ( 1 hom. )

Consequence

WNK1
NM_018979.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.424

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 12-753114-G-A is Benign according to our data. Variant chr12-753114-G-A is described in ClinVar as [Benign]. Clinvar id is 310519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.-452G>A		5_prime_UTR_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.-452G>A		5_prime_UTR_variant	Exon 1 of 28	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.-452G>A		5_prime_UTR_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 link	c.-452G>A		5_prime_UTR_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.0457

AC:

6927

AN:

151530

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0135

Gnomad AMR

AF:

0.0552

Gnomad ASJ

AF:

0.0651

Gnomad EAS

AF:

0.0936

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0775

Gnomad MID

AF:

0.0892

Gnomad NFE

AF:

0.0570

Gnomad OTH

AF:

0.0552

GnomAD4 exome

AF:

0.0479

AC:

AN:

1440

Hom.:

Cov.:

AF XY:

0.0395

AC XY:

AN XY:

784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0263

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0690

AC:

AN:

East Asian (EAS)

AF:

0.0714

AC:

AN:

South Asian (SAS)

AF:

0.0238

AC:

AN:

European-Finnish (FIN)

AF:

0.136

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0518

AC:

AN:

1082

Other (OTH)

AF:

0.0139

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0456

AC:

6920

AN:

151638

Hom.:

210

Cov.:

AF XY:

0.0459

AC XY:

3404

AN XY:

74114

show subpopulations

African (AFR)

AF:

0.0103

AC:

426

AN:

41486

American (AMR)

AF:

0.0552

AC:

841

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.0651

AC:

226

AN:

3472

East Asian (EAS)

AF:

0.0937

AC:

482

AN:

5146

South Asian (SAS)

AF:

0.0259

AC:

125

AN:

4826

European-Finnish (FIN)

AF:

0.0775

AC:

811

AN:

10468

Middle Eastern (MID)

AF:

0.0788

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0570

AC:

3859

AN:

67712

Other (OTH)

AF:

0.0547

AC:

115

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

352

703

1055

1406

1758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0208

Hom.:

Bravo

AF:

0.0444

Asia WGS

AF:

0.0330

AC:

112

AN:

3394

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 06, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

-0.42

PromoterAI

0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=300/0

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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12-753114-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over