rs2289116

Positions:

• chr16-56904378-G-A

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.2857-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,611,780 control chromosomes in the GnomAD database, including 11,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1550 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9523 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.471

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]

SLC12A3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-56904378-G-A is Benign according to our data. Variant chr16-56904378-G-A is described in ClinVar as [Benign]. Clinvar id is 255890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56904378-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2857-17G>A		intron_variant		ENST00000563236.6	NP_001119580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2857-17G>A		intron_variant		1	NM_001126108.2	ENSP00000456149.2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20447 AN: 152130 Hom.: 1541 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0881

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.122 AC: 30584 AN: 251486 Hom.: 2014 AF XY: 0.117 AC XY: 15925 AN XY: 135914

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.0732

Gnomad SAS exome AF: 0.0942

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.112 AC: 162796 AN: 1459532 Hom.: 9523 Cov.: 30 AF XY: 0.111 AC XY: 80410 AN XY: 726176

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.0929

Gnomad4 EAS exome AF: 0.0666

Gnomad4 SAS exome AF: 0.0928

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.135 AC: 20485 AN: 152248 Hom.: 1550 Cov.: 32 AF XY: 0.134 AC XY: 10006 AN XY: 74464

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0881

Gnomad4 EAS AF: 0.0715

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.152

Alfa AF: 0.120 Hom.: 220

Bravo AF: 0.142

Asia WGS AF: 0.0920 AC: 317 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, 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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	This variant is associated with the following publications: (PMID: 28008009, 14578305) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial hypokalemia-hypomagnesemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2289116; hg19: chr16-56938290;