rs13306676

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.2179-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,608,166 control chromosomes in the GnomAD database, including 13,540 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 0.11 ( 1085 hom., cov: 28)

Exomes 𝑓: 0.13 ( 12455 hom. )

Consequence

SLC12A3
NM_001126108.2 splice_region, intron

Scores

Splicing: ADA: 0.00004880

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.763

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 16-56887917-C-T is Benign according to our data. Variant chr16-56887917-C-T is described in ClinVar as Benign. ClinVar VariationId is 255885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
SLC12A3	NM_001126108.2 link	c.2179-8C>T	splice_region_variant, intron_variant	Intron 17 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 link	c.2179-8C>T	splice_region_variant, intron_variant	Intron 17 of 25		NP_000330.3
SLC12A3	NM_001126107.2 link	c.2176-8C>T	splice_region_variant, intron_variant	Intron 17 of 25		NP_001119579.2
SLC12A3	NM_001410896.1 link	c.2176-8C>T	splice_region_variant, intron_variant	Intron 17 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SLC12A3	ENST00000563236.6 link	c.2179-8C>T	splice_region_variant, intron_variant	Intron 17 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6 link	c.2179-8C>T	splice_region_variant, intron_variant	Intron 17 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5 link	c.2176-8C>T	splice_region_variant, intron_variant	Intron 17 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5 link	c.2176-8C>T	splice_region_variant, intron_variant	Intron 17 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

16781

AN:

150388

Hom.:

1085

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0513

Gnomad AMI

AF:

0.0980

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.0609

Gnomad SAS

AF:

0.0995

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.157

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.127

AC:

31836

AN:

250910

AF XY:

0.129

show subpopulations

Gnomad AFR exome

AF:

0.0511

Gnomad AMR exome

AF:

0.0968

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.0615

Gnomad FIN exome

AF:

0.185

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.128

AC:

186225

AN:

1457674

Hom.:

12455

Cov.:

AF XY:

0.128

AC XY:

92773

AN XY:

725314

show subpopulations

African (AFR)

AF:

0.0483

AC:

1612

AN:

33388

American (AMR)

AF:

0.100

AC:

4485

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4594

AN:

26042

East Asian (EAS)

AF:

0.0465

AC:

1842

AN:

39606

South Asian (SAS)

AF:

0.111

AC:

9607

AN:

86200

European-Finnish (FIN)

AF:

0.187

AC:

9879

AN:

52818

Middle Eastern (MID)

AF:

0.124

AC:

707

AN:

5710

European-Non Finnish (NFE)

AF:

0.132

AC:

145963

AN:

1109114

Other (OTH)

AF:

0.125

AC:

7536

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

7874

15749

23623

31498

39372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5106

10212

15318

20424

25530

<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:

0.112

AC:

16788

AN:

150492

Hom.:

1085

Cov.:

AF XY:

0.114

AC XY:

8341

AN XY:

73382

show subpopulations

African (AFR)

AF:

0.0512

AC:

2104

AN:

41086

American (AMR)

AF:

0.117

AC:

1771

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

620

AN:

3460

East Asian (EAS)

AF:

0.0607

AC:

310

AN:

5108

South Asian (SAS)

AF:

0.0997

AC:

472

AN:

4736

European-Finnish (FIN)

AF:

0.183

AC:

1868

AN:

10204

Middle Eastern (MID)

AF:

0.159

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.137

AC:

9263

AN:

67558

Other (OTH)

AF:

0.119

AC:

246

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

626

1252

1878

2504

3130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<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:

0.130

Hom.:

600

Bravo

AF:

0.104

EpiCase

AF:

0.139

EpiControl

AF:

0.138

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Familial hypokalemia-hypomagnesemia

Benign:3

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

Sep 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28008009) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.80

CADD

Benign

0.82

(source)

DANN

Benign

0.55

PhyloP100

-0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.0

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