Genetic Variant WNK3:p.Gln1636Leu (chrX-54202157-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000354646.7(WNK3):c.4907A>T(p.Gln1636Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000896 in 111,549 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1636R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Consequence

WNK3
ENST00000354646.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.28

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10354781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
WNK3	NM_020922.5 link	c.4907A>T	p.Gln1636Leu	missense_variant	Exon 23 of 24	NP_065973.2	Q9BYP7-1
WNK3	NM_001002838.4 link	c.4736A>T	p.Gln1579Leu	missense_variant	Exon 22 of 23	NP_001002838.1	Q9BYP7-3
WNK3	NM_001395166.1 link	c.4736A>T	p.Gln1579Leu	missense_variant	Exon 22 of 23	NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7 link	c.4907A>T	p.Gln1636Leu	missense_variant	Exon 23 of 24	1		ENSP00000346667.2		Q9BYP7-1
WNK3	ENST00000375169.7 link	c.4736A>T	p.Gln1579Leu	missense_variant	Exon 22 of 23	5		ENSP00000364312.3		Q9BYP7-3

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111493

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000379

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111549

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33761

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30712

American (AMR)

AF:

0.00

AC:

AN:

10429

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.000380

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53117

Other (OTH)

AF:

0.00

AC:

AN:

1518

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;T;T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

T;T;.;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.8

.;M;M;.

PhyloP100

4.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.1

N;N;N;.

REVEL

Benign

0.11

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Benign

0.28

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.32

MutPred

0.31

.;Loss of disorder (P = 0.0359);Loss of disorder (P = 0.0359);.;

MVP

0.25

MPC

0.22

ClinPred

0.66

GERP RS

4.9

Varity_R

0.45

gMVP

0.14

Mutation Taster

=95/5

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over