rs5804

Positions:

• chr16-56894607-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.2598C>T​(p.Gly866=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,402 control chromosomes in the GnomAD database, including 9,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (890 hom., cov: 31)
  • Exomes 𝑓: 0.10 (9063 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.55

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 -16 ACMG points.

• BP6: Variant 16-56894607-C-T is Benign according to our data. Variant chr16-56894607-C-T is described in ClinVar as [Benign]. Clinvar id is 255887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56894607-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2598C>T	p.Gly866=	synonymous_variant	22/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2625C>T	p.Gly875=	synonymous_variant	22/26		NP_000330.3
SLC12A3	NM_001126107.2	c.2622C>T	p.Gly874=	synonymous_variant	22/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.2595C>T	p.Gly865=	synonymous_variant	22/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2598C>T	p.Gly866=	synonymous_variant	22/26	1	NM_001126108.2	ENSP00000456149	A1
SLC12A3	ENST00000438926.6	c.2625C>T	p.Gly875=	synonymous_variant	22/26	1		ENSP00000402152	A1
SLC12A3	ENST00000566786.5	c.2622C>T	p.Gly874=	synonymous_variant	22/26	1		ENSP00000457552	P4
SLC12A3	ENST00000262502.5	c.2595C>T	p.Gly865=	synonymous_variant	22/26	5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes AF: 0.0964 AC: 14652 AN: 151988 Hom.: 885 Cov.: 31

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0913

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.126 AC: 31608 AN: 251316 Hom.: 2522 AF XY: 0.123 AC XY: 16740 AN XY: 135818

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.0986

Gnomad NFE exome AF: 0.0897

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.104 AC: 151924 AN: 1461296 Hom.: 9063 Cov.: 32 AF XY: 0.105 AC XY: 76383 AN XY: 726972

Gnomad4 AFR exome AF: 0.0435

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.252

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.0962

Gnomad4 NFE exome AF: 0.0914

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0964 AC: 14664 AN: 152106 Hom.: 890 Cov.: 31 AF XY: 0.101 AC XY: 7476 AN XY: 74342

Gnomad4 AFR AF: 0.0493

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.0933

Gnomad4 NFE AF: 0.0913

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0953 Hom.: 634

Bravo AF: 0.0997

Asia WGS AF: 0.184 AC: 637 AN: 3478

EpiCase AF: 0.0916

EpiControl AF: 0.0953

ClinVar

Significance: Benign

Submissions summary: Benign:10

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 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:3

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+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.0
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5804; hg19: chr16-56928519; COSMIC: COSV52635248;