16-56865289-GC-G
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001126108.2(SLC12A3):c.55del(p.Arg19AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
SLC12A3
NM_001126108.2 frameshift
NM_001126108.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.26
Genes affected
SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 345 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-56865289-GC-G is Pathogenic according to our data. Variant chr16-56865289-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1076450.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | ||
SLC12A3 | NM_001126107.2 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | ||
SLC12A3 | NM_001410896.1 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.55del | p.Arg19AlafsTer8 | frameshift_variant | 1/26 | 5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 20, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with SLC12A3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg19Alafs*8) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.