15-48285112-TAG-T

Variant names:

• chr15-48285112-TAG-T
• rs1057520303
• NM_000338.3:c.2498_2499delGA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000338.3(SLC12A1):​c.2498_2499delGA​(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, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.14
• Publications: 2 publications found

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]

SLC12A1 Gene-Disease associations (from GenCC):

• antenatal Bartter syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Bartter disease type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000309916 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 378050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	NM_000338.3	MANE Select	c.2498_2499delGA	p.Arg833IlefsTer15	frameshift	Exon 21 of 27	NP_000329.2	Q13621-1
	SLC12A1	NM_001184832.2		c.2498_2499delGA	p.Arg833IlefsTer15	frameshift	Exon 21 of 27	NP_001171761.1	Q13621-3
	SLC12A1	NM_001384136.1		c.2498_2499delGA	p.Arg833IlefsTer15	frameshift	Exon 21 of 27	NP_001371065.1	A0A8I5KSK6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	ENST00000380993.8	TSL:5 MANE Select	c.2498_2499delGA	p.Arg833IlefsTer15	frameshift	Exon 21 of 27	ENSP00000370381.3	Q13621-1
	SLC12A1	ENST00000558252.5	TSL:1	n.6621_6622delGA		non_coding_transcript_exon	Exon 17 of 23
	SLC12A1	ENST00000560692.5	TSL:1	n.6637_6638delGA		non_coding_transcript_exon	Exon 16 of 22

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Bartter disease type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057520303; hg19: chr15-48577309;