rs111033591
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_213655.5(WNK1):c.3226C>T(p.Arg1076Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,766 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
WNK1
NM_213655.5 stop_gained
NM_213655.5 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: 1.77
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 12-868697-C-T is Pathogenic according to our data. Variant chr12-868697-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-868697-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WNK1 | NM_213655.5 | c.3226C>T | p.Arg1076Ter | stop_gained | 10/28 | ENST00000340908.9 | |
WNK1 | NM_018979.4 | c.2140-2568C>T | intron_variant | ENST00000315939.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WNK1 | ENST00000340908.9 | c.3226C>T | p.Arg1076Ter | stop_gained | 10/28 | 5 | NM_213655.5 | A2 | |
WNK1 | ENST00000315939.11 | c.2140-2568C>T | intron_variant | 1 | NM_018979.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248942Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135052
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461540Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727052
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This variant is present in population databases (rs111033591, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary sensory and autonomic neuropathy (PMID: 15911806). ClinVar contains an entry for this variant (Variation ID: 5168). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg1076*) in the WNK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WNK1 are known to be pathogenic (PMID: 22910560). - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 11, 2021 | - - |
Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 24, 2005 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2017 | The R1076X nonsense variant in the WNK1 gene has been previously reported, using alternative nomenclature of R290X, as a homozygous variant in a child with HSAN2 (Roddier et al., 2005). The R1076X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, R1076X is interpreted to be a pathogenic variant. - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A
Vest4
GERP RS
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