16-56878020-G-GTCCCTCCC

Position:

• chr16-56878020-G-GTCCCTCCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001126108.2(SLC12A3):​c.1096-50_1096-43dupCCTCCCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 508,590 control chromosomes in the GnomAD database, including 344 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.090 (391 hom., cov: 26)
  • Exomes 𝑓: 0.022 (344 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.837

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0216 (10993/508590) while in subpopulation SAS AF= 0.0478 (2384/49824). AF 95% confidence interval is 0.0462. There are 344 homozygotes in gnomad4_exome. There are 6193 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 344 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1096-50_1096-43dupCCTCCCTC		intron_variant		ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1096-50_1096-43dupCCTCCCTC		intron_variant			NP_000330.3
SLC12A3	NM_001126107.2	c.1093-50_1093-43dupCCTCCCTC		intron_variant			NP_001119579.2
SLC12A3	NM_001410896.1	c.1093-50_1093-43dupCCTCCCTC		intron_variant			NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1096-50_1096-43dupCCTCCCTC		intron_variant		1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1096-50_1096-43dupCCTCCCTC		intron_variant		1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1093-50_1093-43dupCCTCCCTC		intron_variant		1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1093-50_1093-43dupCCTCCCTC		intron_variant		5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8216 AN: 91312 Hom.: 391 Cov.: 26 FAILED QC

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.0216 AC: 10993 AN: 508590 Hom.: 344 AF XY: 0.0234 AC XY: 6193 AN XY: 264392

Gnomad4 AFR exome AF: 0.00519

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.0392

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0899 AC: 8210 AN: 91352 Hom.: 391 Cov.: 26 AF XY: 0.0903 AC XY: 3888 AN XY: 43060

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.0865

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.0573

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0382 Hom.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3217425; hg19: chr16-56911932;