rs8063291

Variant names:

• chr16-56896339-T-C
• rs8063291
• NM_001126108.2:c.2633+1697T>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.2633+1697T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,216 control chromosomes in the GnomAD database, including 3,473 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 0.21 (3473 hom., cov: 33)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.52
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2633+1697T>C		intron_variant	Intron 22 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2660+1697T>C		intron_variant	Intron 22 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.2657+1697T>C		intron_variant	Intron 22 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.2630+1697T>C		intron_variant	Intron 22 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2633+1697T>C		intron_variant	Intron 22 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2660+1697T>C		intron_variant	Intron 22 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2657+1697T>C		intron_variant	Intron 22 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2630+1697T>C		intron_variant	Intron 22 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31983 AN: 152098 Hom.: 3470 Cov.: 33

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.196

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

GnomAD4 genome AF: 0.210 AC: 32014 AN: 152216 Hom.: 3473 Cov.: 33 AF XY: 0.211 AC XY: 15697 AN XY: 74436

African (AFR) AF: 0.275 AC: 11423 AN: 41536

American (AMR) AF: 0.182 AC: 2783 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3466

East Asian (EAS) AF: 0.287 AC: 1486 AN: 5184

South Asian (SAS) AF: 0.192 AC: 928 AN: 4826

European-Finnish (FIN) AF: 0.194 AC: 2059 AN: 10592

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12025 AN: 68000

Other (OTH) AF: 0.198 AC: 419 AN: 2112

Alfa AF: 0.202 Hom.: 1141

Bravo AF: 0.211

Asia WGS AF: 0.279 AC: 970 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	0.52
DANN	Benign	0.25
PhyloP100		-2.5
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: rs8063291; hg19: chr16-56930251;