16-56878020-GTCCC-GTCCCTCCCTCCC

Variant names:

• chr16-56878020-G-GTCCCTCCC
• rs3217425
• NM_001126108.2:c.1096-50_1096-43dupCCTCCCTC

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

SLC12A3 Gene-Disease associations (from GenCC):

• Gitelman syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 6193 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 344 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1096-50_1096-43dupCCTCCCTC		intron_variant	Intron 8 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1096-50_1096-43dupCCTCCCTC		intron_variant	Intron 8 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.1093-50_1093-43dupCCTCCCTC		intron_variant	Intron 8 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.1093-50_1093-43dupCCTCCCTC		intron_variant	Intron 8 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1096-57_1096-56insTCCCTCCC		intron_variant	Intron 8 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1096-57_1096-56insTCCCTCCC		intron_variant	Intron 8 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1093-57_1093-56insTCCCTCCC		intron_variant	Intron 8 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1093-57_1093-56insTCCCTCCC		intron_variant	Intron 8 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 8216 AN: 91312 Hom.: 391 Cov.: 26

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

African (AFR) AF: 0.00519 AC: 62 AN: 11952

American (AMR) AF: 0.0117 AC: 301 AN: 25630

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 361 AN: 10392

East Asian (EAS) AF: 0.0392 AC: 650 AN: 16586

South Asian (SAS) AF: 0.0478 AC: 2384 AN: 49824

European-Finnish (FIN) AF: 0.0204 AC: 364 AN: 17816

Middle Eastern (MID) AF: 0.0284 AC: 46 AN: 1622

European-Non Finnish (NFE) AF: 0.0177 AC: 6236 AN: 351906

Other (OTH) AF: 0.0258 AC: 589 AN: 22862

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

African (AFR) AF: 0.0284 AC: 587 AN: 20664

American (AMR) AF: 0.0865 AC: 737 AN: 8516

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 338 AN: 2324

East Asian (EAS) AF: 0.106 AC: 308 AN: 2896

South Asian (SAS) AF: 0.165 AC: 478 AN: 2900

European-Finnish (FIN) AF: 0.0573 AC: 300 AN: 5236

Middle Eastern (MID) AF: 0.221 AC: 31 AN: 140

European-Non Finnish (NFE) AF: 0.111 AC: 5196 AN: 46882

Other (OTH) AF: 0.108 AC: 131 AN: 1212

Alfa AF: 0.0382 Hom.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3217425; hg19: chr16-56911932;