rs2278489

chr16-56892916-T-Achr16-56892916-T-Cchr16-56892916-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001126108.2(SLC12A3):c.2420-37T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,569,074 control chromosomes in the GnomAD database, including 9,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1616 hom., cov: 35)
  • Exomes 𝑓: 0.10 (8290 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.987

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-56892916-T-A is Benign according to our data. Variant chr16-56892916-T-A is described in ClinVar as [Benign]. Clinvar id is 1182000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.2420-37T>A		intron_variant		ENST00000563236.6
SLC12A3	NM_000339.3	c.2447-37T>A		intron_variant
SLC12A3	NM_001126107.2	c.2444-37T>A		intron_variant
SLC12A3	NM_001410896.1	c.2417-37T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2420-37T>A		intron_variant		1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.2447-37T>A		intron_variant		1		A1
SLC12A3	ENST00000566786.5	c.2444-37T>A		intron_variant		1		P4
SLC12A3	ENST00000262502.5	c.2417-37T>A		intron_variant		5		A1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20253 AN: 152162 Hom.: 1609 Cov.: 35

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.103 AC: 24829 AN: 240136 Hom.: 1426 AF XY: 0.104 AC XY: 13511 AN XY: 130484

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.0921

Gnomad EAS exome AF: 0.0484

Gnomad SAS exome AF: 0.0918

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.105 AC: 148654 AN: 1416794 Hom.: 8290 Cov.: 23 AF XY: 0.105 AC XY: 74001 AN XY: 707094

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.0931

Gnomad4 EAS exome AF: 0.0327

Gnomad4 SAS exome AF: 0.0902

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.133 AC: 20274 AN: 152280 Hom.: 1616 Cov.: 35 AF XY: 0.133 AC XY: 9868 AN XY: 74438

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0873

Gnomad4 EAS AF: 0.0456

Gnomad4 SAS AF: 0.0877

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.136

Alfa AF: 0.0982 Hom.: 2226

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.84
Cadd	Benign	0.37
Dann	Benign	0.77

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: rs2278489; hg19: chr16-56926828;