rs1057520303
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000338.3(SLC12A1):c.2498_2499delGA(p.Arg833fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
SLC12A1
NM_000338.3 frameshift
NM_000338.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.14
Genes affected
SLC12A1 (HGNC:10910): (solute carrier family 12 member 1) This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-48285112-TAG-T is Pathogenic according to our data. Variant chr15-48285112-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 378050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC12A1 | NM_000338.3 | c.2498_2499delGA | p.Arg833fs | frameshift_variant | 21/27 | ENST00000380993.8 | NP_000329.2 | |
SLC12A1 | NM_001184832.2 | c.2498_2499delGA | p.Arg833fs | frameshift_variant | 21/27 | NP_001171761.1 | ||
SLC12A1 | NM_001384136.1 | c.2498_2499delGA | p.Arg833fs | frameshift_variant | 21/27 | NP_001371065.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC12A1 | ENST00000380993.8 | c.2498_2499delGA | p.Arg833fs | frameshift_variant | 21/27 | 5 | NM_000338.3 | ENSP00000370381.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2023 | This sequence change creates a premature translational stop signal (p.Arg833Ilefs*15) in the SLC12A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A1 are known to be pathogenic (PMID: 8640224, 9585600, 19096086). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bartter syndrome (PMID: 28095294, 30790175). ClinVar contains an entry for this variant (Variation ID: 378050). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2024 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28095294, 30790175, 34604727) - |
Bartter disease type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 02, 2017 | - - |
Computational scores
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Calibrated prediction
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Prediction
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