rs6499857

Variant names:

• chr16-56901178-G-C
• rs6499857
• NM_001126108.2:c.2721-1195G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001126108.2(SLC12A3):​c.2721-1195G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 151,888 control chromosomes in the GnomAD database, including 9,286 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (9286 hom., cov: 31)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2721-1195G>C		intron_variant	Intron 23 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2748-1195G>C		intron_variant	Intron 23 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.2745-1195G>C		intron_variant	Intron 23 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.2718-1195G>C		intron_variant	Intron 23 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2721-1195G>C		intron_variant	Intron 23 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2748-1195G>C		intron_variant	Intron 23 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2745-1195G>C		intron_variant	Intron 23 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2718-1195G>C		intron_variant	Intron 23 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46525 AN: 151770 Hom.: 9266 Cov.: 31

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.307 AC: 46595 AN: 151888 Hom.: 9286 Cov.: 31 AF XY: 0.304 AC XY: 22595 AN XY: 74238

African (AFR) AF: 0.581 AC: 24032 AN: 41362

American (AMR) AF: 0.203 AC: 3105 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 868 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1345 AN: 5150

South Asian (SAS) AF: 0.240 AC: 1152 AN: 4808

European-Finnish (FIN) AF: 0.226 AC: 2388 AN: 10562

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12838 AN: 67954

Other (OTH) AF: 0.289 AC: 610 AN: 2110

Alfa AF: 0.268 Hom.: 845

Bravo AF: 0.314

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.61
DANN	Benign	0.35
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6499857; hg19: chr16-56935090;