Genetic Variant NM_213655.5:c.4800C>T (chr12-884848-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_213655.5(WNK1):c.4800C>T(p.Thr1600Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,942 control chromosomes in the GnomAD database, including 18,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1468 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16805 hom. )

Consequence

WNK1
NM_213655.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0490

Publications

22 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, 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=-0.85).

BP6

Variant 12-884848-C-T is Benign according to our data. Variant chr12-884848-C-T is described in ClinVar as Benign. ClinVar VariationId is 137926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.049 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WNK1	NM_213655.5	MANE Plus Clinical	c.4800C>T	p.Thr1600Thr	synonymous	Exon 19 of 28	NP_998820.3
WNK1	NM_018979.4	MANE Select	c.4044C>T	p.Thr1348Thr	synonymous	Exon 19 of 28	NP_061852.3
WNK1	NM_001184985.2		c.4824C>T	p.Thr1608Thr	synonymous	Exon 19 of 28	NP_001171914.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.4800C>T	p.Thr1600Thr	synonymous	Exon 19 of 28	ENSP00000341292.5
WNK1	ENST00000315939.11	TSL:1 MANE Select	c.4044C>T	p.Thr1348Thr	synonymous	Exon 19 of 28	ENSP00000313059.6
WNK1	ENST00000530271.6	TSL:1	c.5283C>T	p.Thr1761Thr	synonymous	Exon 20 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19293

AN:

151970

Hom.:

1465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.128

GnomAD2 exomes

AF:

0.156

AC:

39135

AN:

251332

AF XY:

0.159

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.153

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.148

AC:

215628

AN:

1461854

Hom.:

16805

Cov.:

AF XY:

0.149

AC XY:

108363

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0445

AC:

1490

AN:

33480

American (AMR)

AF:

0.121

AC:

5389

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3723

AN:

26134

East Asian (EAS)

AF:

0.160

AC:

6371

AN:

39700

South Asian (SAS)

AF:

0.172

AC:

14795

AN:

86258

European-Finnish (FIN)

AF:

0.255

AC:

13609

AN:

53418

Middle Eastern (MID)

AF:

0.214

AC:

1235

AN:

5768

European-Non Finnish (NFE)

AF:

0.144

AC:

159885

AN:

1111982

Other (OTH)

AF:

0.151

AC:

9131

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

11989

23979

35968

47958

59947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5710

11420

17130

22840

28550

<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:

0.127

AC:

19302

AN:

152088

Hom.:

1468

Cov.:

AF XY:

0.132

AC XY:

9803

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0495

AC:

2055

AN:

41498

American (AMR)

AF:

0.114

AC:

1736

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

492

AN:

3470

East Asian (EAS)

AF:

0.183

AC:

947

AN:

5166

South Asian (SAS)

AF:

0.164

AC:

792

AN:

4824

European-Finnish (FIN)

AF:

0.266

AC:

2817

AN:

10574

Middle Eastern (MID)

AF:

0.203

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.146

AC:

9953

AN:

67954

Other (OTH)

AF:

0.128

AC:

270

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

861

1722

2584

3445

4306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.135

Hom.:

766

Bravo

AF:

0.112

Asia WGS

AF:

0.154

AC:

538

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.150

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Neuropathy, hereditary sensory and autonomic, type 2A (2)

not provided (1)

Pseudohypoaldosteronism type 2C (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.9

(source)

DANN

Benign

0.40

PhyloP100

-0.049

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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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