Genetic Variant NM_006648.4:c.6319G>A (chr9-93308387-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_006648.4(WNK2):c.6319G>A(p.Val2107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,573,848 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. V2107A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0051 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 45 hom. )

Consequence

WNK2
NM_006648.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

Publications

4 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041105747).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00368 (5229/1421524) while in subpopulation SAS AF = 0.0189 (1525/80628). AF 95% confidence interval is 0.0181. There are 45 homozygotes in GnomAdExome4. There are 2998 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 775 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK2	NM_006648.4 link	c.6319G>A	p.Val2107Ile	missense_variant	Exon 28 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.6319G>A	p.Val2107Ile	missense_variant	Exon 28 of 30	5	NM_006648.4	ENSP00000411181.4		E9PCD1

Frequencies

GnomAD3 genomes

AF:

0.00509

AC:

775

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00975

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00505

AC:

955

AN:

189136

AF XY:

0.00622

show subpopulations

Gnomad AFR exome

AF:

0.00893

Gnomad AMR exome

AF:

0.00207

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.0000737

Gnomad FIN exome

AF:

0.000454

Gnomad NFE exome

AF:

0.00331

Gnomad OTH exome

AF:

0.00377

GnomAD4 exome

AF:

0.00368

AC:

5229

AN:

1421524

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

2998

AN XY:

703362

show subpopulations

African (AFR)

AF:

0.00929

AC:

302

AN:

32510

American (AMR)

AF:

0.00214

AC:

AN:

38340

Ashkenazi Jewish (ASJ)

AF:

0.00397

AC:

101

AN:

25436

East Asian (EAS)

AF:

0.00

AC:

AN:

37242

South Asian (SAS)

AF:

0.0189

AC:

1525

AN:

80628

European-Finnish (FIN)

AF:

0.000438

AC:

AN:

50234

Middle Eastern (MID)

AF:

0.0181

AC:

104

AN:

5732

European-Non Finnish (NFE)

AF:

0.00261

AC:

2851

AN:

1092392

Other (OTH)

AF:

0.00410

AC:

242

AN:

59010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

355

710

1066

1421

1776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.00509

AC:

775

AN:

152324

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

396

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00972

AC:

404

AN:

41572

American (AMR)

AF:

0.00222

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0159

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00318

AC:

216

AN:

68022

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00342

Hom.:

Bravo

AF:

0.00501

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00775

AC:

ESP6500EA

AF:

0.00385

AC:

ExAC

AF:

0.00458

AC:

548

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

T;.

Eigen

Benign

-0.076

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.77

N;.

PhyloP100

3.6

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.48

N;N

REVEL

Benign

0.038

Sift

Benign

0.23

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.68

P;B

Vest4

0.066

MVP

0.28

MPC

0.11

ClinPred

0.0079

GERP RS

3.6

Varity_R

0.051

gMVP

0.075

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over