rs13306676

Positions:

• chr16-56887917-C-T

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.2179-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,608,166 control chromosomes in the GnomAD database, including 13,540 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 0.11 (1085 hom., cov: 28)
  • Exomes 𝑓: 0.13 (12455 hom.)
• Consequence: SLC12A3 NM_001126108.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004880
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.763

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=-0.8).
• BP6: Variant 16-56887917-C-T is Benign according to our data. Variant chr16-56887917-C-T is described in ClinVar as [Benign]. Clinvar id is 255885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56887917-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2179-8C>T		splice_region_variant, intron_variant		ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2179-8C>T		splice_region_variant, intron_variant			NP_000330.3
SLC12A3	NM_001126107.2	c.2176-8C>T		splice_region_variant, intron_variant			NP_001119579.2
SLC12A3	NM_001410896.1	c.2176-8C>T		splice_region_variant, intron_variant			NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2179-8C>T		splice_region_variant, intron_variant		1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2179-8C>T		splice_region_variant, intron_variant		1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2176-8C>T		splice_region_variant, intron_variant		1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2176-8C>T		splice_region_variant, intron_variant		5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16781 AN: 150388 Hom.: 1085 Cov.: 28

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.0980

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0609

Gnomad SAS AF: 0.0995

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.157

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.127 AC: 31836 AN: 250910 Hom.: 2233 AF XY: 0.129 AC XY: 17508 AN XY: 135764

Gnomad AFR exome AF: 0.0511

Gnomad AMR exome AF: 0.0968

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0615

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.128 AC: 186225 AN: 1457674 Hom.: 12455 Cov.: 30 AF XY: 0.128 AC XY: 92773 AN XY: 725314

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.0465

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.112 AC: 16788 AN: 150492 Hom.: 1085 Cov.: 28 AF XY: 0.114 AC XY: 8341 AN XY: 73382

Gnomad4 AFR AF: 0.0512

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.0607

Gnomad4 SAS AF: 0.0997

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.119

Alfa AF: 0.130 Hom.: 600

Bravo AF: 0.104

EpiCase AF: 0.139

EpiControl AF: 0.138

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial hypokalemia-hypomagnesemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2017	- -
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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2019	This variant is associated with the following publications: (PMID: 28008009) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.82
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0
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: rs13306676; hg19: chr16-56921829; COSMIC: COSV52640335;