16-56878991-C-T

Position:

• chr16-56878991-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.1181-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,506,828 control chromosomes in the GnomAD database, including 28,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2524 hom., cov: 32)
  • Exomes 𝑓: 0.19 (25524 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.975

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 16-56878991-C-T is Benign according to our data. Variant chr16-56878991-C-T is described in ClinVar as [Benign]. Clinvar id is 1233940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1181-82C>T		intron_variant		ENST00000563236.6
SLC12A3	NM_000339.3	c.1181-82C>T		intron_variant
SLC12A3	NM_001126107.2	c.1178-82C>T		intron_variant
SLC12A3	NM_001410896.1	c.1178-82C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1181-82C>T		intron_variant		1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1181-82C>T		intron_variant		1		A1
SLC12A3	ENST00000566786.5	c.1178-82C>T		intron_variant		1		P4
SLC12A3	ENST00000262502.5	c.1178-82C>T		intron_variant		5		A1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26942 AN: 152102 Hom.: 2520 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.193 AC: 260995 AN: 1354608 Hom.: 25524 AF XY: 0.194 AC XY: 129936 AN XY: 670716

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.177 AC: 26955 AN: 152220 Hom.: 2524 Cov.: 32 AF XY: 0.181 AC XY: 13493 AN XY: 74408

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.209

Alfa AF: 0.183 Hom.: 4624

Bravo AF: 0.177

Asia WGS AF: 0.236 AC: 818 AN: 3478

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	clinical testing	GeneDx	Aug 06, 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	-0.87
CADD	Benign	0.47
DANN	Benign	0.46

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: rs2289119; hg19: chr16-56912903; COSMIC: COSV52635576;