rs34772420

Positions:

• chr16-56902360-T-C

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.2721-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,760 control chromosomes in the GnomAD database, including 15,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2850 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13108 hom.)
• Consequence: SLC12A3 NM_001126108.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.477

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=-0.87).
• BP6: Variant 16-56902360-T-C is Benign according to our data. Variant chr16-56902360-T-C is described in ClinVar as [Benign]. Clinvar id is 255889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56902360-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.2721-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000563236.6
SLC12A3	NM_000339.3	c.2748-13T>C		splice_polypyrimidine_tract_variant, intron_variant
SLC12A3	NM_001126107.2	c.2745-13T>C		splice_polypyrimidine_tract_variant, intron_variant
SLC12A3	NM_001410896.1	c.2718-13T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2721-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001126108.2	A1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26554 AN: 152006 Hom.: 2844 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.131 AC: 33002 AN: 251386 Hom.: 2597 AF XY: 0.130 AC XY: 17617 AN XY: 135876

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.0742

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0353

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.128 AC: 187541 AN: 1461636 Hom.: 13108 Cov.: 35 AF XY: 0.128 AC XY: 92728 AN XY: 727114

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.0775

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.175 AC: 26584 AN: 152124 Hom.: 2850 Cov.: 31 AF XY: 0.173 AC XY: 12829 AN XY: 74368

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.0390

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.168

Alfa AF: 0.175 Hom.: 510

Bravo AF: 0.177

Asia WGS AF: 0.127 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	-	- -

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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial hypokalemia-hypomagnesemia Benign:2

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.30

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: rs34772420; hg19: chr16-56936272; COSMIC: COSV52637376; COSMIC: COSV52637376;