rs13306677

Variant names:

• chr16-56892283-G-A
• rs13306677
• NM_001126108.2:c.2419+150G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001126108.2(SLC12A3):​c.2419+150G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0888 in 728,526 control chromosomes in the GnomAD database, including 3,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.088 (677 hom., cov: 32)
  • Exomes 𝑓: 0.089 (2504 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0170
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-56892283-G-A is Benign according to our data. Variant chr16-56892283-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 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.2419+150G>A		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2446+123G>A		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2443+123G>A		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.2419+150G>A		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2446+123G>A		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2443+123G>A		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13413 AN: 151954 Hom.: 671 Cov.: 32

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0801

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.0832

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.0889 AC: 51231 AN: 576454 Hom.: 2504 AF XY: 0.0899 AC XY: 28026 AN XY: 311800

African (AFR) AF: 0.0751 AC: 1227 AN: 16344

American (AMR) AF: 0.0564 AC: 2012 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 1601 AN: 18936

East Asian (EAS) AF: 0.0304 AC: 1012 AN: 33338

South Asian (SAS) AF: 0.0836 AC: 5486 AN: 65640

European-Finnish (FIN) AF: 0.119 AC: 4130 AN: 34628

Middle Eastern (MID) AF: 0.124 AC: 377 AN: 3032

European-Non Finnish (NFE) AF: 0.0962 AC: 32574 AN: 338526

Other (OTH) AF: 0.0927 AC: 2812 AN: 30330

GnomAD4 genome AF: 0.0883 AC: 13432 AN: 152072 Hom.: 677 Cov.: 32 AF XY: 0.0897 AC XY: 6665 AN XY: 74334

African (AFR) AF: 0.0743 AC: 3084 AN: 41486

American (AMR) AF: 0.0800 AC: 1221 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 281 AN: 3470

East Asian (EAS) AF: 0.0448 AC: 231 AN: 5160

South Asian (SAS) AF: 0.0832 AC: 401 AN: 4818

European-Finnish (FIN) AF: 0.125 AC: 1326 AN: 10602

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0975 AC: 6630 AN: 67972

Other (OTH) AF: 0.0987 AC: 208 AN: 2108

Alfa AF: 0.0936 Hom.: 619

Bravo AF: 0.0841

Asia WGS AF: 0.0620 AC: 215 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		-0.017
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs13306677;

hg19: chr16-56926195;