rs2304483

Variant names:

• chr16-56884041-T-C
• rs2304483
• NM_001126108.2:c.1670-8T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-56884041-T-C
• chr16-56884041-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.1670-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,464 control chromosomes in the GnomAD database, including 138,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19518 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118989 hom.)
• Consequence: SLC12A3 NM_001126108.2 splice_region, intron
• Scores: Splicing: ADA: 0.000007520
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.223
• Publications: 22 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-56884041-T-C is Benign according to our data. Variant chr16-56884041-T-C is described in ClinVar as Benign. ClinVar VariationId is 255880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.1670-8T>C		splice_region intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1670-8T>C		splice_region intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1667-8T>C		splice_region intron	N/A	NP_001119579.2	P55017-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1670-8T>C		splice_region intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1670-8T>C		splice_region intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1667-8T>C		splice_region intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74255 AN: 151986 Hom.: 19481 Cov.: 32

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.460 AC: 114710 AN: 249478 AF XY: 0.451

Gnomad AFR exome AF: 0.680

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.590

Gnomad FIN exome AF: 0.477

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.396 AC: 578790 AN: 1461360 Hom.: 118989 Cov.: 41 AF XY: 0.397 AC XY: 288964 AN XY: 727000

African (AFR) AF: 0.690 AC: 23089 AN: 33472

American (AMR) AF: 0.527 AC: 23559 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 12725 AN: 26128

East Asian (EAS) AF: 0.597 AC: 23696 AN: 39700

South Asian (SAS) AF: 0.474 AC: 40871 AN: 86244

European-Finnish (FIN) AF: 0.474 AC: 25300 AN: 53398

Middle Eastern (MID) AF: 0.507 AC: 2919 AN: 5752

European-Non Finnish (NFE) AF: 0.361 AC: 400841 AN: 1111582

Other (OTH) AF: 0.427 AC: 25790 AN: 60378

GnomAD4 genome AF: 0.489 AC: 74349 AN: 152104 Hom.: 19518 Cov.: 32 AF XY: 0.495 AC XY: 36797 AN XY: 74338

African (AFR) AF: 0.677 AC: 28089 AN: 41506

American (AMR) AF: 0.493 AC: 7545 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1654 AN: 3468

East Asian (EAS) AF: 0.599 AC: 3091 AN: 5160

South Asian (SAS) AF: 0.468 AC: 2255 AN: 4818

European-Finnish (FIN) AF: 0.481 AC: 5086 AN: 10584

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25168 AN: 67962

Other (OTH) AF: 0.491 AC: 1036 AN: 2110

Alfa AF: 0.417 Hom.: 40630

Bravo AF: 0.497

Asia WGS AF: 0.597 AC: 2073 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.384

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial hypokalemia-hypomagnesemia (5)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.94
DANN	Benign	0.31
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000075
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs2304483; hg19: chr16-56917953; COSMIC: COSV52633349;