rs34880640

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000315939.11(WNK1):​c.446C>T​(p.Ala149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,586,632 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 29 hom. )

Consequence

WNK1
ENST00000315939.11 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.808
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WNK1. . Gene score misZ 2.1626 (greater than the threshold 3.09). Trascript score misZ 4.652 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory and autonomic, type 2A, hereditary sensory and autonomic neuropathy type 2, pseudohypoaldosteronism type 2C.
BP4
Computational evidence support a benign effect (MetaRNN=0.0026817322).
BP6
Variant 12-754011-C-T is Benign according to our data. Variant chr12-754011-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00143 (218/152310) while in subpopulation EAS AF= 0.0329 (170/5160). AF 95% confidence interval is 0.0289. There are 1 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 29 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNK1NM_213655.5 linkuse as main transcriptc.446C>T p.Ala149Val missense_variant 1/28 ENST00000340908.9 NP_998820.3
WNK1NM_018979.4 linkuse as main transcriptc.446C>T p.Ala149Val missense_variant 1/28 ENST00000315939.11 NP_061852.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNK1ENST00000340908.9 linkuse as main transcriptc.446C>T p.Ala149Val missense_variant 1/285 NM_213655.5 ENSP00000341292 A2Q9H4A3-5
WNK1ENST00000315939.11 linkuse as main transcriptc.446C>T p.Ala149Val missense_variant 1/281 NM_018979.4 ENSP00000313059 P2Q9H4A3-1

Frequencies

GnomAD3 genomes
AF:
0.00144
AC:
219
AN:
152192
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0331
Gnomad SAS
AF:
0.00683
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00332
AC:
638
AN:
191920
Hom.:
6
AF XY:
0.00337
AC XY:
354
AN XY:
104938
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000355
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0321
Gnomad SAS exome
AF:
0.00615
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000100
Gnomad OTH exome
AF:
0.000398
GnomAD4 exome
AF:
0.00142
AC:
2031
AN:
1434322
Hom.:
29
Cov.:
94
AF XY:
0.00156
AC XY:
1113
AN XY:
711426
show subpopulations
Gnomad4 AFR exome
AF:
0.0000913
Gnomad4 AMR exome
AF:
0.0000253
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0343
Gnomad4 SAS exome
AF:
0.00595
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000582
Gnomad4 OTH exome
AF:
0.00255
GnomAD4 genome
AF:
0.00143
AC:
218
AN:
152310
Hom.:
1
Cov.:
33
AF XY:
0.00165
AC XY:
123
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0329
Gnomad4 SAS
AF:
0.00683
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000266
Hom.:
1
Bravo
AF:
0.00139
ESP6500AA
AF:
0.000234
AC:
1
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.00280
AC:
334
Asia WGS
AF:
0.0150
AC:
53
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2C Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 14, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
11
DANN
Benign
0.93
DEOGEN2
Benign
0.095
T;.;T;.;.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.77
T;T;T;T;T;T
MetaRNN
Benign
0.0027
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
.;N;N;N;N;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.2
N;N;N;.;N;N
REVEL
Benign
0.037
Sift
Benign
0.57
T;T;T;.;T;T
Sift4G
Benign
0.33
T;.;T;T;T;T
Polyphen
0.0030
B;.;B;.;.;B
Vest4
0.028
MVP
0.18
MPC
0.73
ClinPred
0.0085
T
GERP RS
-1.4
Varity_R
0.021
gMVP
0.13

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.

Other links and lift over

dbSNP: rs34880640; hg19: chr12-863177; API