rs146845953
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001126108.2(SLC12A3):c.2470T>A(p.Ser824Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000838 in 1,614,216 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S824S) has been classified as Likely benign.
Frequency
Consequence
NM_001126108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.2470T>A | p.Ser824Thr | missense_variant | 21/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.2497T>A | p.Ser833Thr | missense_variant | 21/26 | ||
SLC12A3 | NM_001126107.2 | c.2494T>A | p.Ser832Thr | missense_variant | 21/26 | ||
SLC12A3 | NM_001410896.1 | c.2467T>A | p.Ser823Thr | missense_variant | 21/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.2470T>A | p.Ser824Thr | missense_variant | 21/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.2497T>A | p.Ser833Thr | missense_variant | 21/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.2494T>A | p.Ser832Thr | missense_variant | 21/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.2467T>A | p.Ser823Thr | missense_variant | 21/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000552 AC: 84AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000398 AC: 100AN: 251062Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135762
GnomAD4 exome AF: 0.000868 AC: 1269AN: 1461856Hom.: 1 Cov.: 31 AF XY: 0.000818 AC XY: 595AN XY: 727230
GnomAD4 genome ? AF: 0.000551 AC: 84AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41AN XY: 74504
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 14, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2024 | Reported in the heterozygous state in an individual with Gitelman syndrome, but a second SLC12A3 variant was not identified in this individual (PMID: 22009145); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25841442, 34604727, 22009145) - |
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2022 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 833 of the SLC12A3 protein (p.Ser833Thr). This variant is present in population databases (rs146845953, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 22009145). ClinVar contains an entry for this variant (Variation ID: 448393). 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 SLC12A3 protein function. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 09, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at