chr16-56872714-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001126108.2(SLC12A3):c.1023C>T(p.Phe341Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,210 control chromosomes in the GnomAD database, including 851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 186 hom., cov: 33)

Exomes 𝑓: 0.026 ( 665 hom. )

Consequence

SLC12A3
NM_001126108.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.64

Publications

10 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 16-56872714-C-T is Benign according to our data. Variant chr16-56872714-C-T is described in ClinVar as Benign. ClinVar VariationId is 255876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.64 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.1023C>T	p.Phe341Phe	synonymous_variant	Exon 8 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.1023C>T	p.Phe341Phe	synonymous_variant	Exon 8 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.1020C>T	p.Phe340Phe	synonymous_variant	Exon 8 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.1020C>T	p.Phe340Phe	synonymous_variant	Exon 8 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.1023C>T	p.Phe341Phe	synonymous_variant	Exon 8 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.1023C>T	p.Phe341Phe	synonymous_variant	Exon 8 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.1020C>T	p.Phe340Phe	synonymous_variant	Exon 8 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.1020C>T	p.Phe340Phe	synonymous_variant	Exon 8 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

6316

AN:

152228

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0740

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0495

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.0485

Gnomad SAS

AF:

0.0513

Gnomad FIN

AF:

0.0363

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0353

AC:

8871

AN:

251464

AF XY:

0.0347

show subpopulations

Gnomad AFR exome

AF:

0.0696

Gnomad AMR exome

AF:

0.0490

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0481

Gnomad FIN exome

AF:

0.0368

Gnomad NFE exome

AF:

0.0205

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0262

AC:

38264

AN:

1461864

Hom.:

665

Cov.:

AF XY:

0.0269

AC XY:

19586

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0737

AC:

2468

AN:

33480

American (AMR)

AF:

0.0466

AC:

2084

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0191

AC:

500

AN:

26136

East Asian (EAS)

AF:

0.0351

AC:

1393

AN:

39700

South Asian (SAS)

AF:

0.0540

AC:

4658

AN:

86258

European-Finnish (FIN)

AF:

0.0348

AC:

1857

AN:

53416

Middle Eastern (MID)

AF:

0.0215

AC:

124

AN:

5768

European-Non Finnish (NFE)

AF:

0.0211

AC:

23456

AN:

1111990

Other (OTH)

AF:

0.0285

AC:

1724

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2244

4489

6733

8978

11222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

978

1956

2934

3912

4890

<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:

0.0416

AC:

6332

AN:

152346

Hom.:

186

Cov.:

AF XY:

0.0426

AC XY:

3172

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0742

AC:

3087

AN:

41578

American (AMR)

AF:

0.0495

AC:

757

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3472

East Asian (EAS)

AF:

0.0486

AC:

252

AN:

5182

South Asian (SAS)

AF:

0.0509

AC:

246

AN:

4830

European-Finnish (FIN)

AF:

0.0363

AC:

386

AN:

10624

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1446

AN:

68036

Other (OTH)

AF:

0.0359

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

319

639

958

1278

1597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0248

Hom.:

Bravo

AF:

0.0424

Asia WGS

AF:

0.0470

AC:

165

AN:

3478

EpiCase

AF:

0.0207

EpiControl

AF:

0.0225

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

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. -

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 provided

Benign:3

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

- -

Oct 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.36

CADD

Benign

2.3

(source)

DANN

Benign

0.71

PhyloP100

-1.6

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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