chr16-56879507-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.1336-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,545,154 control chromosomes in the GnomAD database, including 29,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2556 hom., cov: 31)

Exomes 𝑓: 0.19 ( 26690 hom. )

Consequence

SLC12A3
NM_001126108.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.568

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 16-56879507-C-T is Benign according to our data. Variant chr16-56879507-C-T is described in ClinVar as [Benign]. Clinvar id is 1184680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.1336-35C>T	intron_variant	Intron 10 of 25	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.1336-35C>T	intron_variant	Intron 10 of 25		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.1333-35C>T	intron_variant	Intron 10 of 25		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.1333-35C>T	intron_variant	Intron 10 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.1336-35C>T	intron_variant	Intron 10 of 25	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.1336-35C>T	intron_variant	Intron 10 of 25	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.1333-35C>T	intron_variant	Intron 10 of 25	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.1333-35C>T	intron_variant	Intron 10 of 25	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27125

AN:

151950

Hom.:

2551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.134

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.201

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.204

AC:

50771

AN:

248760

AF XY:

0.203

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.268

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.194

AC:

269618

AN:

1393086

Hom.:

26690

Cov.:

AF XY:

0.195

AC XY:

135554

AN XY:

696936

show subpopulations

African (AFR)

AF:

0.110

AC:

3555

AN:

32224

American (AMR)

AF:

0.267

AC:

11877

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

4991

AN:

25698

East Asian (EAS)

AF:

0.275

AC:

10821

AN:

39392

South Asian (SAS)

AF:

0.214

AC:

18199

AN:

84904

European-Finnish (FIN)

AF:

0.203

AC:

10570

AN:

52074

Middle Eastern (MID)

AF:

0.234

AC:

1320

AN:

5632

European-Non Finnish (NFE)

AF:

0.187

AC:

196767

AN:

1050480

Other (OTH)

AF:

0.198

AC:

11518

AN:

58156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

11989

23978

35966

47955

59944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6864

13728

20592

27456

34320

<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:

0.178

AC:

27139

AN:

152068

Hom.:

2556

Cov.:

AF XY:

0.183

AC XY:

13569

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.117

AC:

4851

AN:

41514

American (AMR)

AF:

0.248

AC:

3786

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

667

AN:

3472

East Asian (EAS)

AF:

0.274

AC:

1415

AN:

5164

South Asian (SAS)

AF:

0.215

AC:

1036

AN:

4814

European-Finnish (FIN)

AF:

0.201

AC:

2130

AN:

10580

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12623

AN:

67936

Other (OTH)

AF:

0.212

AC:

446

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1158

2316

3475

4633

5791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.185

Hom.:

505

Bravo

AF:

0.179

Asia WGS

AF:

0.237

AC:

820

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypokalemia-hypomagnesemia

Benign:1

Jul 10, 2021

Genome-Nilou Lab

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

-0.80

CADD

Benign

3.3

(source)

DANN

Benign

0.90

PhyloP100

-0.57

Mutation Taster

=100/0

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

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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