rs34136389

Variant names:

• chr16-56875410-A-G
• rs34136389
• NM_001126108.2:c.1095+2624A>G

Variant summary

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

The NM_001126108.2(SLC12A3):​c.1095+2624A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,064 control chromosomes in the GnomAD database, including 5,224 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 0.26 (5224 hom., cov: 31)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 0 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1095+2624A>G		intron_variant	Intron 8 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1095+2624A>G		intron_variant	Intron 8 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.1092+2624A>G		intron_variant	Intron 8 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.1092+2624A>G		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.1095+2624A>G		intron_variant	Intron 8 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1095+2624A>G		intron_variant	Intron 8 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1092+2624A>G		intron_variant	Intron 8 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1092+2624A>G		intron_variant	Intron 8 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39256 AN: 151946 Hom.: 5216 Cov.: 31

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.258 AC: 39276 AN: 152064 Hom.: 5224 Cov.: 31 AF XY: 0.260 AC XY: 19328 AN XY: 74320

African (AFR) AF: 0.196 AC: 8145 AN: 41494

American (AMR) AF: 0.316 AC: 4835 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3470

East Asian (EAS) AF: 0.353 AC: 1809 AN: 5130

South Asian (SAS) AF: 0.321 AC: 1545 AN: 4812

European-Finnish (FIN) AF: 0.231 AC: 2445 AN: 10586

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18341 AN: 67986

Other (OTH) AF: 0.280 AC: 589 AN: 2102

Alfa AF: 0.268 Hom.: 12240

Bravo AF: 0.264

Asia WGS AF: 0.333 AC: 1154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.5
DANN	Benign	0.69
PhyloP100		-0.025
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: rs34136389; hg19: chr16-56909322;