rs2304479

chr16-56867153-A-Gchr16-56867153-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001126108.2(SLC12A3):c.366A>G(p.Ala122=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,613,832 control chromosomes in the GnomAD database, including 5,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (576 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4939 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.83

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-56867153-A-G is Benign according to our data. Variant chr16-56867153-A-G is described in ClinVar as [Benign]. Clinvar id is 255892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56867153-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.366A>G	p.Ala122=	synonymous_variant	2/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.366A>G	p.Ala122=	synonymous_variant	2/26
SLC12A3	NM_001126107.2	c.363A>G	p.Ala121=	synonymous_variant	2/26
SLC12A3	NM_001410896.1	c.363A>G	p.Ala121=	synonymous_variant	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.366A>G	p.Ala122=	synonymous_variant	2/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.366A>G	p.Ala122=	synonymous_variant	2/26	1		A1
SLC12A3	ENST00000566786.5	c.363A>G	p.Ala121=	synonymous_variant	2/26	1		P4
SLC12A3	ENST00000262502.5	c.363A>G	p.Ala121=	synonymous_variant	2/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9394 AN: 152118 Hom.: 578 Cov.: 33

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0521

Gnomad OTH AF: 0.0742

GnomAD3 exomes AF: 0.0963 AC: 24050 AN: 249630 Hom.: 2088 AF XY: 0.0935 AC XY: 12638 AN XY: 135230

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.0463

Gnomad NFE exome AF: 0.0485

Gnomad OTH exome AF: 0.0696

GnomAD4 exome AF: 0.0668 AC: 97585 AN: 1461596 Hom.: 4939 Cov.: 33 AF XY: 0.0684 AC XY: 49702 AN XY: 727092

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.0328

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.0456

Gnomad4 NFE exome AF: 0.0540

Gnomad4 OTH exome AF: 0.0727

GnomAD4 genome AF: 0.0617 AC: 9397 AN: 152236 Hom.: 576 Cov.: 33 AF XY: 0.0662 AC XY: 4927 AN XY: 74438

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0441

Gnomad4 NFE AF: 0.0521

Gnomad4 OTH AF: 0.0753

Alfa AF: 0.0555 Hom.: 403

Bravo AF: 0.0677

Asia WGS AF: 0.196 AC: 680 AN: 3478

EpiCase AF: 0.0517

EpiControl AF: 0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:4

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	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -

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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.1
Dann	Benign	0.47

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: rs2304479; hg19: chr16-56901065; COSMIC: COSV52638279;