Variant 9-93247703-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006648.4(WNK2):c.1703C>T(p.Pro568Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000754 in 1,564,372 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

WNK2
NM_006648.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008107215).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK2	NM_006648.4 linkuse as main transcript	c.1703C>T	p.Pro568Leu	missense_variant	8/30	ENST00000427277.7	NP_006639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK2	ENST00000427277.7 linkuse as main transcript	c.1703C>T	p.Pro568Leu	missense_variant	8/30	5	NM_006648.4	ENSP00000411181	A2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000226

AC:

AN:

172742

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

92228

show subpopulations

Gnomad AFR exome

AF:

0.000106

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000799

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000175

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000421

GnomAD4 exome

AF:

0.0000687

AC:

AN:

1412312

Hom.:

Cov.:

AF XY:

0.0000573

AC XY:

AN XY:

697596

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00103

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.000183

Gnomad4 NFE exome

AF:

0.00000828

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.000138

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000762

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.1703C>T (p.P568L) alteration is located in exon 7 (coding exon 7) of the WNK2 gene. This alteration results from a C to T substitution at nucleotide position 1703, causing the proline (P) at amino acid position 568 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.29

.;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.0081

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.79

.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.14

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.82, 0.77

.;P;P

Vest4

0.17, 0.16

MVP

0.093

MPC

0.14

ClinPred

0.061

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over