rs2304483

chr16-56884041-T-Cchr16-56884041-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):c.1670-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,464 control chromosomes in the GnomAD database, including 138,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19518 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118989 hom.)
• Consequence: SLC12A3 NM_001126108.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000007520
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.223

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-56884041-T-C is Benign according to our data. Variant chr16-56884041-T-C is described in ClinVar as [Benign]. Clinvar id is 255880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56884041-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1670-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000563236.6
SLC12A3	NM_000339.3	c.1670-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC12A3	NM_001126107.2	c.1667-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC12A3	NM_001410896.1	c.1667-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1670-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1670-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1
SLC12A3	ENST00000566786.5	c.1667-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P4
SLC12A3	ENST00000262502.5	c.1667-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74255 AN: 151986 Hom.: 19481 Cov.: 32

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.489

GnomAD3 exomes AF: 0.460 AC: 114710 AN: 249478 Hom.: 27576 AF XY: 0.451 AC XY: 60859 AN XY: 134986

Gnomad AFR exome AF: 0.680

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.590

Gnomad SAS exome AF: 0.477

Gnomad FIN exome AF: 0.477

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.396 AC: 578790 AN: 1461360 Hom.: 118989 Cov.: 41 AF XY: 0.397 AC XY: 288964 AN XY: 727000

Gnomad4 AFR exome AF: 0.690

Gnomad4 AMR exome AF: 0.527

Gnomad4 ASJ exome AF: 0.487

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.474

Gnomad4 NFE exome AF: 0.361

Gnomad4 OTH exome AF: 0.427

GnomAD4 genome AF: 0.489 AC: 74349 AN: 152104 Hom.: 19518 Cov.: 32 AF XY: 0.495 AC XY: 36797 AN XY: 74338

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.493

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.599

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.491

Alfa AF: 0.407 Hom.: 16945

Bravo AF: 0.497

Asia WGS AF: 0.597 AC: 2073 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.384

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2019	This variant is associated with the following publications: (PMID: 28325561, 31398183, 24776766) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.94
Dann	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000075
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs2304483; hg19: chr16-56917953; COSMIC: COSV52633349;