rs2304479

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001126108.2(SLC12A3):c.366A>G(p.Ala122Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,613,832 control chromosomes in the GnomAD database, including 5,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 576 hom., cov: 33)

Exomes 𝑓: 0.067 ( 4939 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.83

Publications

14 publications found

Variant links:

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)

SLC12A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-56867153-A-G is Benign according to our data. Variant chr16-56867153-A-G is described in ClinVar as Benign. ClinVar VariationId is 255892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.83 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.366A>G	p.Ala122Ala	synonymous_variant	Exon 2 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.366A>G	p.Ala122Ala	synonymous_variant	Exon 2 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.363A>G	p.Ala121Ala	synonymous_variant	Exon 2 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.363A>G	p.Ala121Ala	synonymous_variant	Exon 2 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.366A>G	p.Ala122Ala	synonymous_variant	Exon 2 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.366A>G	p.Ala122Ala	synonymous_variant	Exon 2 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.363A>G	p.Ala121Ala	synonymous_variant	Exon 2 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.363A>G	p.Ala121Ala	synonymous_variant	Exon 2 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0618

AC:

9394

AN:

152118

Hom.:

578

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0521

Gnomad OTH

AF:

0.0742

GnomAD2 exomes

AF:

0.0963

AC:

24050

AN:

249630

AF XY:

0.0935

show subpopulations

Gnomad AFR exome

AF:

0.0176

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.0353

Gnomad EAS exome

AF:

0.304

Gnomad FIN exome

AF:

0.0463

Gnomad NFE exome

AF:

0.0485

Gnomad OTH exome

AF:

0.0696

GnomAD4 exome

AF:

0.0668

AC:

97585

AN:

1461596

Hom.:

4939

Cov.:

AF XY:

0.0684

AC XY:

49702

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.0193

AC:

646

AN:

33480

American (AMR)

AF:

0.195

AC:

8704

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.0328

AC:

857

AN:

26122

East Asian (EAS)

AF:

0.239

AC:

9490

AN:

39686

South Asian (SAS)

AF:

0.124

AC:

10716

AN:

86238

European-Finnish (FIN)

AF:

0.0456

AC:

2432

AN:

53348

Middle Eastern (MID)

AF:

0.0493

AC:

284

AN:

5766

European-Non Finnish (NFE)

AF:

0.0540

AC:

60064

AN:

1111932

Other (OTH)

AF:

0.0727

AC:

4392

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

5312

10624

15935

21247

26559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2544

5088

7632

10176

12720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0617

AC:

9397

AN:

152236

Hom.:

576

Cov.:

AF XY:

0.0662

AC XY:

4927

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0199

AC:

828

AN:

41550

American (AMR)

AF:

0.136

AC:

2087

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.297

AC:

1531

AN:

5156

South Asian (SAS)

AF:

0.124

AC:

600

AN:

4832

European-Finnish (FIN)

AF:

0.0441

AC:

468

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0521

AC:

3542

AN:

68010

Other (OTH)

AF:

0.0753

AC:

159

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

448

896

1344

1792

2240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0553

Hom.:

431

Bravo

AF:

0.0677

Asia WGS

AF:

0.196

AC:

680

AN:

3478

EpiCase

AF:

0.0517

EpiControl

AF:

0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.1

(source)

DANN

Benign

0.47

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over