rs150358489

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2

The NM_001126108.2(SLC12A3):c.1210G>A(p.Val404Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V404V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.435

Publications

0 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 -13 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001126108.2

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043110847).

BP6

Variant 16-56879102-G-A is Benign according to our data. Variant chr16-56879102-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC12A3	NM_001126108.2 link	c.1210G>A	p.Val404Ile	missense_variant	Exon 10 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 link	c.1210G>A	p.Val404Ile	missense_variant	Exon 10 of 26		NP_000330.3
SLC12A3	NM_001126107.2 link	c.1207G>A	p.Val403Ile	missense_variant	Exon 10 of 26		NP_001119579.2
SLC12A3	NM_001410896.1 link	c.1207G>A	p.Val403Ile	missense_variant	Exon 10 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC12A3	ENST00000563236.6 link	c.1210G>A	p.Val404Ile	missense_variant	Exon 10 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6 link	c.1210G>A	p.Val404Ile	missense_variant	Exon 10 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5 link	c.1207G>A	p.Val403Ile	missense_variant	Exon 10 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5 link	c.1207G>A	p.Val403Ile	missense_variant	Exon 10 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

273

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000497

AC:

124

AN:

249412

AF XY:

0.000333

show subpopulations

Gnomad AFR exome

AF:

0.00687

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000175

AC:

255

AN:

1460808

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.00616

AC:

206

AN:

33468

American (AMR)

AF:

0.000471

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111730

Other (OTH)

AF:

0.000365

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00179

AC:

272

AN:

152310

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00628

AC:

261

AN:

41558

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000790

Hom.:

Bravo

AF:

0.00204

ESP6500AA

AF:

0.00751

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000511

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

- -

Familial hypokalemia-hypomagnesemia

Benign:1

Jul 15, 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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

9.3

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.49

.;.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

.;N;N;.

PhyloP100

0.43

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.010

N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.31

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.035

MVP

0.71

MPC

0.071

ClinPred

0.0038

GERP RS

1.1

Varity_R

0.036

gMVP

0.58

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over