NM_001126108.2:c.2598C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.2598C>T(p.Gly866Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,402 control chromosomes in the GnomAD database, including 9,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.096 ( 890 hom., cov: 31)

Exomes 𝑓: 0.10 ( 9063 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.55

Publications

25 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 16-56894607-C-T is Benign according to our data. Variant chr16-56894607-C-T is described in ClinVar as Benign. ClinVar VariationId is 255887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2598C>T	p.Gly866Gly	synonymous_variant	Exon 22 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2625C>T	p.Gly875Gly	synonymous_variant	Exon 22 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2622C>T	p.Gly874Gly	synonymous_variant	Exon 22 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2595C>T	p.Gly865Gly	synonymous_variant	Exon 22 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.2598C>T	p.Gly866Gly	synonymous_variant	Exon 22 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.2625C>T	p.Gly875Gly	synonymous_variant	Exon 22 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.2622C>T	p.Gly874Gly	synonymous_variant	Exon 22 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.2595C>T	p.Gly865Gly	synonymous_variant	Exon 22 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0964

AC:

14652

AN:

151988

Hom.:

885

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.231

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.0933

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0913

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.126

AC:

31608

AN:

251316

AF XY:

0.123

show subpopulations

Gnomad AFR exome

AF:

0.0485

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.0986

Gnomad NFE exome

AF:

0.0897

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.104

AC:

151924

AN:

1461296

Hom.:

9063

Cov.:

AF XY:

0.105

AC XY:

76383

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.0435

AC:

1456

AN:

33472

American (AMR)

AF:

0.216

AC:

9664

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

3519

AN:

26120

East Asian (EAS)

AF:

0.252

AC:

10019

AN:

39684

South Asian (SAS)

AF:

0.153

AC:

13223

AN:

86210

European-Finnish (FIN)

AF:

0.0962

AC:

5140

AN:

53408

Middle Eastern (MID)

AF:

0.106

AC:

610

AN:

5768

European-Non Finnish (NFE)

AF:

0.0914

AC:

101574

AN:

1111546

Other (OTH)

AF:

0.111

AC:

6719

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

7061

14121

21182

28242

35303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3940

7880

11820

15760

19700

<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:

0.0964

AC:

14664

AN:

152106

Hom.:

890

Cov.:

AF XY:

0.101

AC XY:

7476

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0493

AC:

2047

AN:

41496

American (AMR)

AF:

0.171

AC:

2617

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

476

AN:

3466

East Asian (EAS)

AF:

0.230

AC:

1189

AN:

5162

South Asian (SAS)

AF:

0.160

AC:

773

AN:

4818

European-Finnish (FIN)

AF:

0.0933

AC:

989

AN:

10598

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0913

AC:

6206

AN:

67978

Other (OTH)

AF:

0.110

AC:

231

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

666

1331

1997

2662

3328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.0953

Hom.:

634

Bravo

AF:

0.0997

Asia WGS

AF:

0.184

AC:

637

AN:

3478

EpiCase

AF:

0.0916

EpiControl

AF:

0.0953

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

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

- -

Jan 13, 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. -

not specified

Benign:3

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.0

(source)

DANN

Benign

0.63

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: 35

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