16-56870675-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5PP2BP4_StrongBP6_Very_StrongBA1

The NM_001126108.2(SLC12A3):c.791C>G(p.Ala264Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,613,832 control chromosomes in the GnomAD database, including 758,043 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A264D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.98 ( 72928 hom., cov: 30)

Exomes 𝑓: 0.97 ( 685115 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.10

Publications

54 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 -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-56870675-C-GCGTGGTCTCGGTCATTGG is described in ClinVar as Pathogenic. ClinVar VariationId is 2577273.Status of the report is criteria_provided_single_submitter, 1 stars.

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=8.947269E-7).

BP6

Variant 16-56870675-C-G is Benign according to our data. Variant chr16-56870675-C-G is described in ClinVar as Benign. ClinVar VariationId is 504886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC12A3	NM_001126108.2 link	c.791C>G	p.Ala264Gly	missense_variant	Exon 6 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 link	c.791C>G	p.Ala264Gly	missense_variant	Exon 6 of 26		NP_000330.3
SLC12A3	NM_001126107.2 link	c.788C>G	p.Ala263Gly	missense_variant	Exon 6 of 26		NP_001119579.2
SLC12A3	NM_001410896.1 link	c.788C>G	p.Ala263Gly	missense_variant	Exon 6 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC12A3	ENST00000563236.6 link	c.791C>G	p.Ala264Gly	missense_variant	Exon 6 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6 link	c.791C>G	p.Ala264Gly	missense_variant	Exon 6 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5 link	c.788C>G	p.Ala263Gly	missense_variant	Exon 6 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5 link	c.788C>G	p.Ala263Gly	missense_variant	Exon 6 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes

AF:

0.979

AC:

148873

AN:

152110

Hom.:

72869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.989

Gnomad ASJ

AF:

0.993

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.996

Gnomad FIN

AF:

0.967

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.965

Gnomad OTH

AF:

0.987

GnomAD2 exomes

AF:

0.978

AC:

245970

AN:

251456

AF XY:

0.978

show subpopulations

Gnomad AFR exome

AF:

0.994

Gnomad AMR exome

AF:

0.995

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.969

Gnomad NFE exome

AF:

0.964

Gnomad OTH exome

AF:

0.981

GnomAD4 exome

AF:

0.968

AC:

1414989

AN:

1461604

Hom.:

685115

Cov.:

AF XY:

0.969

AC XY:

704391

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.996

AC:

33328

AN:

33478

American (AMR)

AF:

0.994

AC:

44456

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

25982

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39683

AN:

39696

South Asian (SAS)

AF:

0.992

AC:

85594

AN:

86256

European-Finnish (FIN)

AF:

0.968

AC:

51728

AN:

53420

Middle Eastern (MID)

AF:

0.995

AC:

5737

AN:

5768

European-Non Finnish (NFE)

AF:

0.962

AC:

1069482

AN:

1111736

Other (OTH)

AF:

0.977

AC:

58999

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2134

4268

6401

8535

10669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21634

43268

64902

86536

108170

<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:

0.979

AC:

148991

AN:

152228

Hom.:

72928

Cov.:

AF XY:

0.979

AC XY:

72886

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.994

AC:

41280

AN:

41540

American (AMR)

AF:

0.989

AC:

15135

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.993

AC:

3448

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5162

AN:

5162

South Asian (SAS)

AF:

0.996

AC:

4800

AN:

4820

European-Finnish (FIN)

AF:

0.967

AC:

10257

AN:

10608

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

0.965

AC:

65622

AN:

68004

Other (OTH)

AF:

0.987

AC:

2085

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

164

328

492

656

820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.971

Hom.:

49136

Bravo

AF:

0.981

TwinsUK

AF:

0.966

AC:

3582

ALSPAC

AF:

0.960

AC:

3698

ESP6500AA

AF:

0.993

AC:

4364

ESP6500EA

AF:

0.963

AC:

8284

ExAC

AF:

0.976

AC:

118445

Asia WGS

AF:

0.996

AC:

3463

AN:

3476

EpiCase

AF:

0.969

EpiControl

AF:

0.970

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Feb 17, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.791C) is the minor allele. This al lele (C) has been identified in 3.65% (2438/66728) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs15 29927) and thus meets criteria to be classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Dec 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25892104, 17460608, 10988270, 15480096, 27884173, 11940055, 20981092, 14766743, 21415153, 22245519) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.026

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.24

DEOGEN2

Uncertain

0.53

.;.;D;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.70

T;T;T;T

MetaRNN

Benign

8.9e-7

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.0

.;N;N;.

PhyloP100

8.1

PrimateAI

Uncertain

0.69

PROVEAN

Benign

5.7

N;N;N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.081

MPC

0.087

ClinPred

0.016

GERP RS

4.9

Varity_R

0.081

gMVP

0.92

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over