Variant 9-93185192-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006648.4(WNK2):c.263G>T(p.Arg88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,171,546 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 2 hom. )

Consequence

WNK2
NM_006648.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0550

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14736149).

BS2

High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK2	NM_006648.4 linkuse as main transcript	c.263G>T	p.Arg88Leu	missense_variant	2/30	ENST00000427277.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK2	ENST00000427277.7 linkuse as main transcript	c.263G>T	p.Arg88Leu	missense_variant	2/30	5	NM_006648.4	A2

Frequencies

GnomAD3 genomes

AF:

0.000698

AC:

104

AN:

148920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000626

AC:

AN:

1022518

Hom.:

Cov.:

AF XY:

0.0000514

AC XY:

AN XY:

486300

show subpopulations

Gnomad4 AFR exome

AF:

0.00271

Gnomad4 AMR exome

AF:

0.000296

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000226

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000698

AC:

104

AN:

149028

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

AN XY:

72700

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000706

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

Jan 10, 2023

The c.263G>T (p.R88L) alteration is located in exon 1 (coding exon 1) of the WNK2 gene. This alteration results from a G to T substitution at nucleotide position 263, causing the arginine (R) at amino acid position 88 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.048

.;T;.

Eigen

Benign

-0.028

Eigen_PC

Benign

-0.013

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.80

T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

2.0

.;M;.

MutationTaster

Benign

1.0

D;D;D;N;N

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0030

D;D;D

Sift4G

Benign

0.36

T;T;T

Polyphen

0.91, 0.95

.;P;P

Vest4

0.093, 0.20

MutPred

0.39

Loss of methylation at R88 (P = 0.0185);Loss of methylation at R88 (P = 0.0185);Loss of methylation at R88 (P = 0.0185);

MVP

0.043

MPC

1.7

ClinPred

0.73

GERP RS

3.7

Varity_R

0.23

gMVP

0.43

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