Genetic Variant WNK2:p.Pro687Leu (chr9-93256324-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006648.4(WNK2):c.2060C>T(p.Pro687Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,579,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

WNK2
NM_006648.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Publications

2 publications found

Variant links:

Genes affected

WNK2 (HGNC:14542): (WNK lysine deficient protein kinase 2) The protein encoded by this gene is a cytoplasmic serine-threonine kinase that belongs to the protein kinase superfamily. The protein plays an important role in the regulation of electrolyte homeostasis, cell signaling survival, and proliferation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

WNK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.133351).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK2	NM_006648.4 link	c.2060C>T	p.Pro687Leu	missense_variant	Exon 10 of 30	ENST00000427277.7	NP_006639.3	E9PCD1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK2	ENST00000427277.7 link	c.2060C>T	p.Pro687Leu	missense_variant	Exon 10 of 30	5	NM_006648.4	ENSP00000411181.4		E9PCD1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000141

AC:

AN:

198276

AF XY:

0.000164

show subpopulations

Gnomad AFR exome

AF:

0.0000880

Gnomad AMR exome

AF:

0.0000315

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000272

Gnomad OTH exome

AF:

0.000195

GnomAD4 exome

AF:

0.000427

AC:

609

AN:

1427724

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

279

AN XY:

708582

show subpopulations

African (AFR)

AF:

0.0000608

AC:

AN:

32916

American (AMR)

AF:

0.0000235

AC:

AN:

42572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.0000517

AC:

AN:

38684

South Asian (SAS)

AF:

0.00

AC:

AN:

82246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39642

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5114

European-Non Finnish (NFE)

AF:

0.000527

AC:

581

AN:

1101930

Other (OTH)

AF:

0.000388

AC:

AN:

59270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000368

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.000135

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P687L variant (also known as c.2060C>T), located in coding exon 9 of the WNK2 gene, results from a C to T substitution at nucleotide position 2060. The proline at codon 687 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

2.5

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.97

D;D

Vest4

0.18

MVP

0.18

MPC

0.14

ClinPred

0.46

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.078

gMVP

0.17

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over