16-56865276-CTT-C

Position:

• chr16-56865276-CTT-C

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.43_44del​(p.Leu15ValfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T14T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC12A3 NM_001126108.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.02

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 345 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-56865276-CTT-C is Pathogenic according to our data. Variant chr16-56865276-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1339518.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.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26
SLC12A3	NM_001126107.2	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26
SLC12A3	NM_001410896.1	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26	1		A1
SLC12A3	ENST00000566786.5	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26	1		P4
SLC12A3	ENST00000262502.5	c.43_44del	p.Leu15ValfsTer14	frameshift_variant	1/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56899188;