Genetic Variant NM_018979.4:c.2490G>A (chr12-879689-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018979.4(WNK1):c.2490G>A(p.Pro830Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,440 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 4 hom., cov: 29)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

WNK1
NM_018979.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.29

Publications

4 publications found

Variant links:

Genes affected

WNK1 (HGNC:14540): (WNK lysine deficient protein kinase 1) This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.[provided by RefSeq, May 2010]

WNK1 Gene-Disease associations (from GenCC):

neuropathy, hereditary sensory and autonomic, type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pseudohypoaldosteronism type 2C
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary sensory and autonomic neuropathy type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WNK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 12-879689-G-A is Benign according to our data. Variant chr12-879689-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00213 (323/151608) while in subpopulation AMR AF = 0.00893 (136/15226). AF 95% confidence interval is 0.00771. There are 4 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018979.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WNK1	NM_018979.4	MANE Select	c.2490G>A	p.Pro830Pro	synonymous	Exon 11 of 28	NP_061852.3	Q9H4A3-1
WNK1	NM_213655.5	MANE Plus Clinical	c.3867+1328G>A		intron	N/A	NP_998820.3	Q9H4A3-5
WNK1	NM_001184985.2		c.3613-1032G>A		intron	N/A	NP_001171914.1	Q9H4A3-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2490G>A	p.Pro830Pro	synonymous	Exon 11 of 28	ENSP00000313059.6	Q9H4A3-1
WNK1	ENST00000530271.6	TSL:1	c.3729G>A	p.Pro1243Pro	synonymous	Exon 12 of 31	ENSP00000433548.3	Q9H4A3-7
WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.3867+1328G>A		intron	N/A	ENSP00000341292.5	Q9H4A3-5

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

323

AN:

151492

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00894

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00217

Gnomad OTH

AF:

0.00241

GnomAD2 exomes

AF:

0.00179

AC:

449

AN:

251442

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00212

AC:

3100

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1519

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00411

AC:

184

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000185

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00245

AC:

2720

AN:

1111976

Other (OTH)

AF:

0.00205

AC:

124

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00213

AC:

323

AN:

151608

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

180

AN XY:

74082

show subpopulations

African (AFR)

AF:

0.000653

AC:

AN:

41324

American (AMR)

AF:

0.00893

AC:

136

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000209

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00217

AC:

147

AN:

67888

Other (OTH)

AF:

0.00239

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00198

Hom.:

Bravo

AF:

0.00241

EpiCase

AF:

0.00196

EpiControl

AF:

0.00290

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Pseudohypoaldosteronism type 2C (1)

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

WNK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over