chr16-56885363-C-G
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_001126108.2(SLC12A3):c.1924C>G(p.Arg642Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000433 in 1,546,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R642C) has been classified as Pathogenic.
Frequency
Consequence
NM_001126108.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.1924C>G | p.Arg642Gly | missense_variant, splice_region_variant | 15/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.1924C>G | p.Arg642Gly | missense_variant, splice_region_variant | 15/26 | ||
SLC12A3 | NM_001126107.2 | c.1921C>G | p.Arg641Gly | missense_variant, splice_region_variant | 15/26 | ||
SLC12A3 | NM_001410896.1 | c.1921C>G | p.Arg641Gly | missense_variant, splice_region_variant | 15/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.1924C>G | p.Arg642Gly | missense_variant, splice_region_variant | 15/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.1924C>G | p.Arg642Gly | missense_variant, splice_region_variant | 15/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.1921C>G | p.Arg641Gly | missense_variant, splice_region_variant | 15/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.1921C>G | p.Arg641Gly | missense_variant, splice_region_variant | 15/26 | 5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000252 AC: 4AN: 158898Hom.: 0 AF XY: 0.0000239 AC XY: 2AN XY: 83662
GnomAD4 exome AF: 0.0000359 AC: 50AN: 1393890Hom.: 0 Cov.: 29 AF XY: 0.0000378 AC XY: 26AN XY: 688230
GnomAD4 genome AF: 0.000112 AC: 17AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74338
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Dec 15, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP | Apr 27, 2022 | ACMG criteria used:PS4, PM1, PM2, PM3, PM5, PP3, PP5 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.R642G in SLC12A3 (NM_000339.3) has been previously reported in affected patients (Syren ML et al; Corbetta S et al). The variant was submitted to ClinVar as Pathogenic. The p.R642G variant is observed in 4/62,126 (0.0064%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R642G missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 642 of SLC12A3 is conserved in all mammalian species. The nucleotide c.1924 in SLC12A3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. In the absence of functional studies this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 03, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12112667, 31028937, 22009145, 11168953, 20675610, 25422309, 11408395, 32397528, 33542107, 34604727, 34768847, 35894287, 36302598, 34532947, 34373523, 35785516) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 642 of the SLC12A3 protein (p.Arg642Gly). This variant is present in population databases (rs200697179, gnomAD 0.007%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 11408395, 12112667, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 397523). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at