12-753198-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_018979.4(WNK1):c.-368G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 188,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00090 ( 0 hom. )

Consequence

WNK1
NM_018979.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.260

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000712 (107/150344) while in subpopulation AMR AF = 0.00151 (23/15214). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5 link	c.-368G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.-368G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4
WNK1	NM_213655.5 link	c.-368G>T	5_prime_UTR_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 link	c.-368G>T	5_prime_UTR_variant	Exon 1 of 28	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
WNK1	ENST00000340908.9 link	c.-368G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5	Q9H4A3-5
WNK1	ENST00000315939.11 link	c.-368G>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6	Q9H4A3-1
WNK1	ENST00000340908.9 link	c.-368G>T	5_prime_UTR_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5	Q9H4A3-5
WNK1	ENST00000315939.11 link	c.-368G>T	5_prime_UTR_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6	Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.000712

AC:

107

AN:

150234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000376

Gnomad OTH

AF:

0.000483

GnomAD4 exome

AF:

0.000898

AC:

AN:

37862

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

AN XY:

19178

show subpopulations

African (AFR)

AF:

0.000752

AC:

AN:

1330

American (AMR)

AF:

0.00

AC:

AN:

810

Ashkenazi Jewish (ASJ)

AF:

0.00675

AC:

AN:

1630

East Asian (EAS)

AF:

0.00

AC:

AN:

2318

South Asian (SAS)

AF:

0.00237

AC:

AN:

1688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000475

AC:

AN:

25250

Other (OTH)

AF:

0.00237

AC:

AN:

2534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.541

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000712

AC:

107

AN:

150344

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

AN XY:

73546

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41390

American (AMR)

AF:

0.00151

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000376

AC:

AN:

66546

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000684

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2C

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.2

(source)

DANN

Benign

0.79

PhyloP100

0.26

PromoterAI

0.0065

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=296/4

polymorphism

(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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12-753198-G-T

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