dbSNP rs35797045: SLC12A3:c.1825+9C>A (chr16-56884213-C-A) – ACMG Classification: Benign (-20 pts)

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.1825+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,613,806 control chromosomes in the GnomAD database, including 1,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 126 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1522 hom. )

Consequence

SLC12A3
NM_001126108.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0800

Publications

5 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: PanelApp Australia, 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=-0.81).

BP6

Variant 16-56884213-C-A is Benign according to our data. Variant chr16-56884213-C-A is described in ClinVar as Benign. ClinVar VariationId is 255881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC12A3	NM_001126108.2	MANE Select	c.1825+9C>A	intron	N/A	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3		c.1825+9C>A	intron	N/A	NP_000330.3	P55017-2
SLC12A3	NM_001126107.2		c.1822+9C>A	intron	N/A	NP_001119579.2	P55017-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1825+9C>A	intron	N/A	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6	TSL:1	c.1825+9C>A	intron	N/A	ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5	TSL:1	c.1822+9C>A	intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5091

AN:

152160

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0444

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0166

Gnomad FIN

AF:

0.0833

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0458

Gnomad OTH

AF:

0.0326

GnomAD2 exomes

AF:

0.0338

AC:

8409

AN:

249056

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.00628

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0443

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0806

Gnomad NFE exome

AF:

0.0424

Gnomad OTH exome

AF:

0.0443

GnomAD4 exome

AF:

0.0424

AC:

61929

AN:

1461528

Hom.:

1522

Cov.:

AF XY:

0.0417

AC XY:

30302

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.00732

AC:

245

AN:

33478

American (AMR)

AF:

0.0194

AC:

866

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0454

AC:

1186

AN:

26126

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0169

AC:

1459

AN:

86258

European-Finnish (FIN)

AF:

0.0779

AC:

4146

AN:

53254

Middle Eastern (MID)

AF:

0.0574

AC:

331

AN:

5766

European-Non Finnish (NFE)

AF:

0.0462

AC:

51317

AN:

1111844

Other (OTH)

AF:

0.0393

AC:

2374

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2953

5907

8860

11814

14767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1898

3796

5694

7592

9490

<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:

0.0334

AC:

5089

AN:

152278

Hom.:

126

Cov.:

AF XY:

0.0347

AC XY:

2586

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00813

AC:

338

AN:

41574

American (AMR)

AF:

0.0282

AC:

431

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

154

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0168

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0833

AC:

884

AN:

10618

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0458

AC:

3111

AN:

67996

Other (OTH)

AF:

0.0318

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

254

508

763

1017

1271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0397

Hom.:

253

Bravo

AF:

0.0282

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hypokalemia-hypomagnesemia (4)

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.3

(source)

DANN

Benign

0.42

PhyloP100

-0.080

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over