Genetic Variant SLC12A3:c.2925-372T>C (chr16-56912892-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001126108.2(SLC12A3):c.2925-372T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 151,786 control chromosomes in the GnomAD database, including 29,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 29201 hom., cov: 30)

Consequence

SLC12A3
NM_001126108.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2925-372T>C	intron_variant	Intron 25 of 25	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2952-372T>C	intron_variant	Intron 25 of 25		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2949-372T>C	intron_variant	Intron 25 of 25		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2922-372T>C	intron_variant	Intron 25 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 link	c.2925-372T>C		intron_variant	Intron 25 of 25	1	NM_001126108.2	ENSP00000456149.2		P55017-1

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92426

AN:

151668

Hom.:

29181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.557

Gnomad ASJ

AF:

0.562

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.483

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.551

Gnomad OTH

AF:

0.615

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.609

AC:

92491

AN:

151786

Hom.:

29201

Cov.:

AF XY:

0.608

AC XY:

45056

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.777

AC:

32135

AN:

41356

American (AMR)

AF:

0.557

AC:

8497

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.562

AC:

1948

AN:

3466

East Asian (EAS)

AF:

0.316

AC:

1627

AN:

5148

South Asian (SAS)

AF:

0.483

AC:

2315

AN:

4790

European-Finnish (FIN)

AF:

0.621

AC:

6549

AN:

10548

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.551

AC:

37435

AN:

67906

Other (OTH)

AF:

0.610

AC:

1284

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1648

3297

4945

6594

8242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.569

Hom.:

41429

Bravo

AF:

0.610

Asia WGS

AF:

0.460

AC:

1599

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.14

(source)

DANN

Benign

0.38

PhyloP100

-1.2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over