rs34772420

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.2721-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,760 control chromosomes in the GnomAD database, including 15,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2850 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13108 hom. )

Consequence

SLC12A3
NM_001126108.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.477

Publications

9 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=-0.87).

BP6

Variant 16-56902360-T-C is Benign according to our data. Variant chr16-56902360-T-C is described in ClinVar as [Benign]. Clinvar id is 255889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2721-13T>C	intron_variant	Intron 23 of 25	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2748-13T>C	intron_variant	Intron 23 of 25		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2745-13T>C	intron_variant	Intron 23 of 25		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2718-13T>C	intron_variant	Intron 23 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 link	c.2721-13T>C		intron_variant	Intron 23 of 25	1	NM_001126108.2	ENSP00000456149.2		P55017-1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26554

AN:

152006

Hom.:

2844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.299

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.0393

Gnomad SAS

AF:

0.0996

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.166

GnomAD2 exomes

AF:

0.131

AC:

33002

AN:

251386

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.0742

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.0353

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.128

AC:

187541

AN:

1461636

Hom.:

13108

Cov.:

AF XY:

0.128

AC XY:

92728

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.309

AC:

10341

AN:

33476

American (AMR)

AF:

0.0775

AC:

3466

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

3981

AN:

26130

East Asian (EAS)

AF:

0.0232

AC:

922

AN:

39700

South Asian (SAS)

AF:

0.110

AC:

9476

AN:

86254

European-Finnish (FIN)

AF:

0.148

AC:

7920

AN:

53382

Middle Eastern (MID)

AF:

0.132

AC:

759

AN:

5760

European-Non Finnish (NFE)

AF:

0.128

AC:

142628

AN:

1111832

Other (OTH)

AF:

0.133

AC:

8048

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

8669

17339

26008

34678

43347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.175

AC:

26584

AN:

152124

Hom.:

2850

Cov.:

AF XY:

0.173

AC XY:

12829

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.298

AC:

12373

AN:

41456

American (AMR)

AF:

0.118

AC:

1806

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

539

AN:

3468

East Asian (EAS)

AF:

0.0390

AC:

202

AN:

5178

South Asian (SAS)

AF:

0.100

AC:

483

AN:

4826

European-Finnish (FIN)

AF:

0.147

AC:

1555

AN:

10590

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9122

AN:

67990

Other (OTH)

AF:

0.168

AC:

354

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1045

2091

3136

4182

5227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.175

Hom.:

510

Bravo

AF:

0.177

Asia WGS

AF:

0.127

AC:

440

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Familial hypokalemia-hypomagnesemia

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.7

(source)

DANN

Benign

0.30

PhyloP100

-0.48

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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rs34772420

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