rs1057520303

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.14
Variant links:
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
SLC12A1NM_000338.3 linkuse as main transcriptc.2498_2499delGA p.Arg833fs frameshift_variant 21/27 ENST00000380993.8 NP_000329.2 Q13621-1Q8IUN5
SLC12A1NM_001184832.2 linkuse as main transcriptc.2498_2499delGA p.Arg833fs frameshift_variant 21/27 NP_001171761.1 Q13621-3B4DPF4
SLC12A1NM_001384136.1 linkuse as main transcriptc.2498_2499delGA p.Arg833fs frameshift_variant 21/27 NP_001371065.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC12A1ENST00000380993.8 linkuse as main transcriptc.2498_2499delGA p.Arg833fs frameshift_variant 21/275 NM_000338.3 ENSP00000370381.3 Q13621-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 09, 2023This 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 submitterclinical testingGeneDxMay 26, 2024Frameshift 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 providedliterature onlyOMIMMar 02, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057520303; hg19: chr15-48577309; API