rs201766777

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PP2PP3BP4BP6

The NM_018979.4(WNK1):​c.5869C>T​(p.Arg1957Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000314 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1957H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 29)
Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

WNK1
NM_018979.4 missense

Scores

9
6
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.57
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 Uncertain_significance. Variant got 0 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.
PP3
Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.36727896).
BP6
Variant 12-896356-C-T is Benign according to our data. Variant chr12-896356-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 306612.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNK1NM_213655.5 linkuse as main transcriptc.6625C>T p.Arg2209Cys missense_variant 24/28 ENST00000340908.9 NP_998820.3 Q9H4A3-5
WNK1NM_018979.4 linkuse as main transcriptc.5869C>T p.Arg1957Cys missense_variant 24/28 ENST00000315939.11 NP_061852.3 Q9H4A3-1A5D8Z4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNK1ENST00000340908.9 linkuse as main transcriptc.6625C>T p.Arg2209Cys missense_variant 24/285 NM_213655.5 ENSP00000341292.5 Q9H4A3-5
WNK1ENST00000315939.11 linkuse as main transcriptc.5869C>T p.Arg1957Cys missense_variant 24/281 NM_018979.4 ENSP00000313059.6 Q9H4A3-1

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152108
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000394
AC:
99
AN:
251330
Hom.:
1
AF XY:
0.000390
AC XY:
53
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000947
Gnomad FIN exome
AF:
0.000508
Gnomad NFE exome
AF:
0.000396
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.000322
AC:
470
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.000319
AC XY:
232
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000742
Gnomad4 FIN exome
AF:
0.000768
Gnomad4 NFE exome
AF:
0.000296
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152226
Hom.:
0
Cov.:
29
AF XY:
0.000134
AC XY:
10
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000368
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000464
Hom.:
1
Bravo
AF:
0.000257
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000404
AC:
49
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 26, 2022The p.R2209C variant (also known as c.6625C>T), located in coding exon 24 of the WNK1 gene, results from a C to T substitution at nucleotide position 6625. The arginine at codon 2209 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Pseudohypoaldosteronism type 2C Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;.;D;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.37
T;T;T;T;T
MetaSVM
Uncertain
0.45
D
MutationAssessor
Uncertain
2.1
.;.;M;.;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-5.2
D;.;D;.;D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D;.;D;.;D
Sift4G
Benign
0.070
T;.;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.81
MVP
0.72
MPC
0.66
ClinPred
0.17
T
GERP RS
5.9
Varity_R
0.48
gMVP
0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201766777; hg19: chr12-1005522; COSMIC: COSV60044341; COSMIC: COSV60044341; API