dbSNP rs199996615: WNK3:p.Ala1748Val (chrX-54198484-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The ENST00000354646.7(WNK3):c.5243C>T(p.Ala1748Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000941 in 1,190,815 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000088 ( 0 hom. 36 hem. )

Consequence

WNK3
ENST00000354646.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.94

Publications

2 publications found

Variant links:

Genes affected

WNK3 (HGNC:14543): (WNK lysine deficient protein kinase 3) This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

WNK3 Gene-Disease associations (from GenCC):

Prieto syndrome
Inheritance: XL Classification: MODERATE Submitted by: G2P

WNK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.085945606).

BP6

Variant X-54198484-G-A is Benign according to our data. Variant chrX-54198484-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660657.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
WNK3	NM_020922.5 link	c.5243C>T	p.Ala1748Val	missense_variant	Exon 24 of 24	NP_065973.2	Q9BYP7-1
WNK3	NM_001002838.4 link	c.5072C>T	p.Ala1691Val	missense_variant	Exon 23 of 23	NP_001002838.1	Q9BYP7-3
WNK3	NM_001395166.1 link	c.5072C>T	p.Ala1691Val	missense_variant	Exon 23 of 23	NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7 link	c.5243C>T	p.Ala1748Val	missense_variant	Exon 24 of 24	1		ENSP00000346667.2		Q9BYP7-1
WNK3	ENST00000375169.7 link	c.5072C>T	p.Ala1691Val	missense_variant	Exon 23 of 23	5		ENSP00000364312.3		Q9BYP7-3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

107275

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000716

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000294

Gnomad SAS

AF:

0.000420

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000960

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

181620

AF XY:

0.000136

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000877

AC:

AN:

1083493

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

354467

show subpopulations

African (AFR)

AF:

0.000115

AC:

AN:

26081

American (AMR)

AF:

0.000314

AC:

AN:

35042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19258

East Asian (EAS)

AF:

0.00

AC:

AN:

30094

South Asian (SAS)

AF:

0.000112

AC:

AN:

53388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40447

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.0000820

AC:

AN:

829518

Other (OTH)

AF:

0.000132

AC:

AN:

45566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000158

AC:

AN:

107322

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

30198

show subpopulations

African (AFR)

AF:

0.000102

AC:

AN:

29414

American (AMR)

AF:

0.000715

AC:

AN:

9791

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2605

East Asian (EAS)

AF:

0.000295

AC:

AN:

3395

South Asian (SAS)

AF:

0.000422

AC:

AN:

2371

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5381

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.0000961

AC:

AN:

52051

Other (OTH)

AF:

0.00

AC:

AN:

1439

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000221

EpiControl

AF:

0.000180

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WNK3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

.;T;T;.

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.55

T;T;.;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.086

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L;L;.

PhyloP100

3.9

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N;N;.

REVEL

Benign

0.11

Sift

Uncertain

0.019

D;D;D;.

Sift4G

Benign

0.078

T;T;T;T

Polyphen

0.052

B;B;B;.

Vest4

0.12

MVP

0.21

MPC

0.21

ClinPred

0.044

GERP RS

5.5

Varity_R

0.083

gMVP

0.26

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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rs199996615

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