16-56879542-AC-A

Position:

• chr16-56879542-AC-A

Variant summary

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

The ENST00000563236.6(SLC12A3):​c.1338del​(p.Met447Ter) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A3 ENST00000563236.6 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.550

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]

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 16-56879542-AC-A is Pathogenic according to our data. Variant chr16-56879542-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 279587.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1338del	p.Met447Ter	frameshift_variant, splice_region_variant	11/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1338del	p.Met447Ter	frameshift_variant, splice_region_variant	11/26		NP_000330.3
SLC12A3	NM_001126107.2	c.1335del	p.Met446Ter	frameshift_variant, splice_region_variant	11/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1335del	p.Met446Ter	frameshift_variant, splice_region_variant	11/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1338del	p.Met447Ter	frameshift_variant, splice_region_variant	11/26	1	NM_001126108.2	ENSP00000456149	A1
SLC12A3	ENST00000438926.6	c.1338del	p.Met447Ter	frameshift_variant, splice_region_variant	11/26	1		ENSP00000402152	A1
SLC12A3	ENST00000566786.5	c.1335del	p.Met446Ter	frameshift_variant, splice_region_variant	11/26	1		ENSP00000457552	P4
SLC12A3	ENST00000262502.5	c.1335del	p.Met446Ter	frameshift_variant, splice_region_variant	11/26	5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Aug 16, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886041108; hg19: chr16-56913454;