rs1057520303

Positions:

• chr15-48285112-TAG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000338.3(SLC12A1):​c.2498_2499del​(p.Arg833IlefsTer15) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A1	NM_000338.3	c.2498_2499del	p.Arg833IlefsTer15	frameshift_variant	21/27	ENST00000380993.8
SLC12A1	NM_001184832.2	c.2498_2499del	p.Arg833IlefsTer15	frameshift_variant	21/27
SLC12A1	NM_001384136.1	c.2498_2499del	p.Arg833IlefsTer15	frameshift_variant	21/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A1	ENST00000380993.8	c.2498_2499del	p.Arg833IlefsTer15	frameshift_variant	21/27	5	NM_000338.3	A1

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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bartter disease type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 02, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1057520303; hg19: chr15-48577309;