rs772771448
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_213655.5(WNK1):c.2105C>A(p.Ser702Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,613,984 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
WNK1
NM_213655.5 missense
NM_213655.5 missense
Scores
9
9
Clinical Significance
Conservation
PhyloP100: 3.97
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, WNK1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3764529).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WNK1 | NM_213655.5 | c.2105C>A | p.Ser702Tyr | missense_variant | 8/28 | ENST00000340908.9 | |
WNK1 | NM_018979.4 | c.2105C>A | p.Ser702Tyr | missense_variant | 8/28 | ENST00000315939.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WNK1 | ENST00000340908.9 | c.2105C>A | p.Ser702Tyr | missense_variant | 8/28 | 5 | NM_213655.5 | A2 | |
WNK1 | ENST00000315939.11 | c.2105C>A | p.Ser702Tyr | missense_variant | 8/28 | 1 | NM_018979.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251318Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135820
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GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57AN XY: 727208
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 18, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2023 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 702 of the WNK1 protein (p.Ser702Tyr). This variant is present in population databases (rs772771448, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with WNK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 538520). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WNK1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2021 | The p.S702Y variant (also known as c.2105C>A), located in coding exon 8 of the WNK1 gene, results from a C to A substitution at nucleotide position 2105. The serine at codon 702 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;N;D
REVEL
Benign
Sift
Uncertain
D;D;D;.;D;D
Sift4G
Uncertain
D;.;T;T;T;D
Polyphen
D;.;D;.;.;.
Vest4
MutPred
Loss of glycosylation at S702 (P = 0.0107);Loss of glycosylation at S702 (P = 0.0107);Loss of glycosylation at S702 (P = 0.0107);Loss of glycosylation at S702 (P = 0.0107);Loss of glycosylation at S702 (P = 0.0107);.;
MVP
MPC
0.15
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at