16-56892881-C-T

Position:

• chr16-56892881-C-T

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.2420-72C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,245,246 control chromosomes in the GnomAD database, including 24,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4333 hom., cov: 33)
  • Exomes 𝑓: 0.17 (20332 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04

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 16-56892881-C-T is Benign according to our data. Variant chr16-56892881-C-T is described in ClinVar as [Benign]. Clinvar id is 1228533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2420-72C>T		intron_variant		ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2447-72C>T		intron_variant			NP_000330.3
SLC12A3	NM_001126107.2	c.2444-72C>T		intron_variant			NP_001119579.2
SLC12A3	NM_001410896.1	c.2417-72C>T		intron_variant			NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2420-72C>T		intron_variant		1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2447-72C>T		intron_variant		1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2444-72C>T		intron_variant		1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2417-72C>T		intron_variant		5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32948 AN: 152110 Hom.: 4315 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.172 AC: 187453 AN: 1093018 Hom.: 20332 AF XY: 0.172 AC XY: 95963 AN XY: 557894

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.518

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.217 AC: 32994 AN: 152228 Hom.: 4333 Cov.: 33 AF XY: 0.221 AC XY: 16413 AN XY: 74414

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.222

Alfa AF: 0.137 Hom.: 1831

Bravo AF: 0.231

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.56

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: rs2278490; hg19: chr16-56926793;