rs2399594

Variant names:

• chr16-56912285-A-G
• rs2399594
• NM_001126108.2:c.2925-979A>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.2925-979A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 152,180 control chromosomes in the GnomAD database, including 11,780 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 0.39 (11780 hom., cov: 34)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 9 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2925-979A>G		intron_variant	Intron 25 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2952-979A>G		intron_variant	Intron 25 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.2949-979A>G		intron_variant	Intron 25 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.2922-979A>G		intron_variant	Intron 25 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2925-979A>G		intron_variant	Intron 25 of 25	1	NM_001126108.2	ENSP00000456149.2

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59517 AN: 152062 Hom.: 11779 Cov.: 34

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.399

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

GnomAD4 genome AF: 0.391 AC: 59535 AN: 152180 Hom.: 11780 Cov.: 34 AF XY: 0.391 AC XY: 29092 AN XY: 74388

African (AFR) AF: 0.428 AC: 17767 AN: 41518

American (AMR) AF: 0.349 AC: 5333 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1217 AN: 3472

East Asian (EAS) AF: 0.237 AC: 1228 AN: 5176

South Asian (SAS) AF: 0.271 AC: 1307 AN: 4826

European-Finnish (FIN) AF: 0.446 AC: 4725 AN: 10592

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26685 AN: 67982

Other (OTH) AF: 0.397 AC: 837 AN: 2110

Alfa AF: 0.385 Hom.: 11616

Bravo AF: 0.387

Asia WGS AF: 0.287 AC: 999 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.010
DANN	Benign	0.69
PhyloP100		-2.3
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: rs2399594; hg19: chr16-56946197;