rs35797045

Positions:

• chr16-56884213-C-A
• chr16-56884213-C-G

Variant summary

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

The ENST00000563236.6(SLC12A3):​c.1825+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,613,806 control chromosomes in the GnomAD database, including 1,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (126 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1522 hom.)
• Consequence: SLC12A3 ENST00000563236.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0800

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=-0.81).
• BP6: Variant 16-56884213-C-A is Benign according to our data. Variant chr16-56884213-C-A is described in ClinVar as [Benign]. Clinvar id is 255881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56884213-C-A is described in Lovd as [Benign]. Variant chr16-56884213-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1825+9C>A		intron_variant		ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1825+9C>A		intron_variant			NP_000330.3
SLC12A3	NM_001126107.2	c.1822+9C>A		intron_variant			NP_001119579.2
SLC12A3	NM_001410896.1	c.1822+9C>A		intron_variant			NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1825+9C>A		intron_variant		1	NM_001126108.2	ENSP00000456149	A1
SLC12A3	ENST00000438926.6	c.1825+9C>A		intron_variant		1		ENSP00000402152	A1
SLC12A3	ENST00000566786.5	c.1822+9C>A		intron_variant		1		ENSP00000457552	P4
SLC12A3	ENST00000262502.5	c.1822+9C>A		intron_variant		5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5091 AN: 152160 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.00813

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0833

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0338 AC: 8409 AN: 249056 Hom.: 190 AF XY: 0.0346 AC XY: 4661 AN XY: 134852

Gnomad AFR exome AF: 0.00628

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0443

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.0806

Gnomad NFE exome AF: 0.0424

Gnomad OTH exome AF: 0.0443

GnomAD4 exome AF: 0.0424 AC: 61929 AN: 1461528 Hom.: 1522 Cov.: 34 AF XY: 0.0417 AC XY: 30302 AN XY: 727074

Gnomad4 AFR exome AF: 0.00732

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.0454

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0779

Gnomad4 NFE exome AF: 0.0462

Gnomad4 OTH exome AF: 0.0393

GnomAD4 genome AF: 0.0334 AC: 5089 AN: 152278 Hom.: 126 Cov.: 32 AF XY: 0.0347 AC XY: 2586 AN XY: 74442

Gnomad4 AFR AF: 0.00813

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.0833

Gnomad4 NFE AF: 0.0458

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0389 Hom.: 109

Bravo AF: 0.0282

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	- -
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	-0.81
CADD	Benign	4.3
DANN	Benign	0.42

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: rs35797045; hg19: chr16-56918125;