16-56865269-G-GA

Position:

• chr16-56865269-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.35dup​(p.Asp12GlufsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D12D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.98

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 346 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-56865269-G-GA is Pathogenic according to our data. Variant chr16-56865269-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 975084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26
SLC12A3	NM_001126107.2	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26
SLC12A3	NM_001410896.1	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26	1		A1
SLC12A3	ENST00000566786.5	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26	1		P4
SLC12A3	ENST00000262502.5	c.35dup	p.Asp12GlufsTer18	frameshift_variant	1/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461496 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 19, 2018	A heterozygous frameshift insertion variant, NM_000339.2(SLC12A3):c.35dupA, has been identified in exon 1 of 26 of the SLC12A3 gene. This insertion is predicted to create a frameshift starting at amino acid position 12, introducing a stop codon 18 residues downstream (NP_000330.2(SLC12A3):p.(Asp12Glufs*18)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. However, truncation of the protein as a result of a NMD-escape mechanism has not been excluded. The variant is absent in population databases (gnomAD, dbSNP, 1000G), and has not been previously reported in clinical cases. However, a number of different LoF variants downstream have been reported as pathogenic (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2023

This sequence change creates a premature translational stop signal (p.Asp12Glufs*18) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Gitelman syndrome (PMID: 26306968). This variant is also known as c.35_36insA. ClinVar contains an entry for this variant (Variation ID: 975084). 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)		0.0		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: rs1964322654; hg19: chr16-56899181;