16-56904475-C-T

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.2924+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,610,364 control chromosomes in the GnomAD database, including 61,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9829 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51339 hom. )

Consequence

SLC12A3
NM_001126108.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.86

Publications

13 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 links:

MIR6863 (HGNC:49942): (microRNA 6863) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6863 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=-0.87).

BP6

Variant 16-56904475-C-T is Benign according to our data. Variant chr16-56904475-C-T is described in ClinVar as Benign. ClinVar VariationId is 255891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2924+13C>T		intron_variant	Intron 25 of 25	ENST00000563236.6	NP_001119580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 link	c.2924+13C>T		intron_variant	Intron 25 of 25	1	NM_001126108.2	ENSP00000456149.2

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51195

AN:

152016

Hom.:

9813

Cov.:

show subpopulations

Gnomad AFR

AF:

0.532

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.305

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.304

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.283

AC:

71033

AN:

251334

AF XY:

0.277

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.306

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.135

Gnomad FIN exome

AF:

0.302

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.298

GnomAD4 exome

AF:

0.259

AC:

377208

AN:

1458230

Hom.:

51339

Cov.:

AF XY:

0.258

AC XY:

187100

AN XY:

725562

show subpopulations

African (AFR)

AF:

0.543

AC:

18117

AN:

33336

American (AMR)

AF:

0.300

AC:

13420

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

8243

AN:

26066

East Asian (EAS)

AF:

0.113

AC:

4473

AN:

39622

South Asian (SAS)

AF:

0.251

AC:

21629

AN:

86208

European-Finnish (FIN)

AF:

0.304

AC:

16223

AN:

53320

Middle Eastern (MID)

AF:

0.333

AC:

1913

AN:

5738

European-Non Finnish (NFE)

AF:

0.250

AC:

276747

AN:

1109034

Other (OTH)

AF:

0.273

AC:

16443

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

13702

27404

41106

54808

68510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9402

18804

28206

37608

47010

<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:

0.337

AC:

51262

AN:

152134

Hom.:

9829

Cov.:

AF XY:

0.336

AC XY:

24974

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.532

AC:

22075

AN:

41488

American (AMR)

AF:

0.305

AC:

4662

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1058

AN:

3470

East Asian (EAS)

AF:

0.136

AC:

703

AN:

5182

South Asian (SAS)

AF:

0.240

AC:

1158

AN:

4820

European-Finnish (FIN)

AF:

0.304

AC:

3226

AN:

10596

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.256

AC:

17429

AN:

67966

Other (OTH)

AF:

0.341

AC:

721

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1647

3293

4940

6586

8233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

490

980

1470

1960

2450

<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:

0.301

Hom.:

2459

Bravo

AF:

0.345

Asia WGS

AF:

0.271

AC:

940

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Mar 06, 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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.2951+13C>T in intron 25 of SLC12A3: This variant is not expected to have clini cal significance because it is not located within the splice consensus sequence and has been identified in 58.70% (776/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs2289115). -

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

- -

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

This variant is associated with the following publications: (PMID: 14578305) -

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

-0.87

CADD

Benign

0.12

(source)

DANN

Benign

0.65

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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