12-896639-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_213655.5(WNK1):c.6908G>T(p.Ser2303Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2303N) has been classified as Uncertain significance.
Frequency
Consequence
NM_213655.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WNK1 | NM_213655.5 | c.6908G>T | p.Ser2303Ile | missense_variant | 24/28 | ENST00000340908.9 | |
WNK1 | NM_018979.4 | c.6152G>T | p.Ser2051Ile | missense_variant | 24/28 | ENST00000315939.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WNK1 | ENST00000340908.9 | c.6908G>T | p.Ser2303Ile | missense_variant | 24/28 | 5 | NM_213655.5 | A2 | |
WNK1 | ENST00000315939.11 | c.6152G>T | p.Ser2051Ile | missense_variant | 24/28 | 1 | NM_018979.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 28
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248296Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134390
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457928Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725080
GnomAD4 genome ? Cov.: 28
ClinVar
Submissions by phenotype
Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 10, 2017 | This sequence change replaces serine with isoleucine at codon 2051 of the WNK1 protein (p.Ser2051Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs561238194, ExAC 0.002%) but has not been reported in the literature in individuals with a WNK1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at