16-56870675-C-G

Position:

chr16-56870675-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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:9

Conservation

PhyloP100: 8.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity S12A3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001126108.2

PM5

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

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 id is 504886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870675-C-G is described in Lovd as [Benign].

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/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.791C>G	p.Ala264Gly	missense_variant	6/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.791C>G	p.Ala264Gly	missense_variant	6/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.788C>G	p.Ala263Gly	missense_variant	6/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.788C>G	p.Ala263Gly	missense_variant	6/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.791C>G	p.Ala264Gly	missense_variant	6/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.791C>G	p.Ala264Gly	missense_variant	6/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.788C>G	p.Ala263Gly	missense_variant	6/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.788C>G	p.Ala263Gly	missense_variant	6/26	5		A1

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

GnomAD3 exomes

AF:

0.978

AC:

245970

AN:

251456

Hom.:

120339

AF XY:

0.978

AC XY:

132883

AN XY:

135912

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 SAS exome

AF:

0.992

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

Gnomad4 AFR exome

AF:

0.996

Gnomad4 AMR exome

AF:

0.994

Gnomad4 ASJ exome

AF:

0.994

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.992

Gnomad4 FIN exome

AF:

0.968

Gnomad4 NFE exome

AF:

0.962

Gnomad4 OTH exome

AF:

0.977

GnomAD4 genome

AF:

0.979

AC:

148991

AN:

152228

Hom.:

72928

Cov.:

AF XY:

0.979

AC XY:

72886

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.994

Gnomad4 AMR

AF:

0.989

Gnomad4 ASJ

AF:

0.993

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.996

Gnomad4 FIN

AF:

0.967

Gnomad4 NFE

AF:

0.965

Gnomad4 OTH

AF:

0.987

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	This variant is associated with the following publications: (PMID: 25892104, 17460608, 10988270, 15480096, 27884173, 11940055, 20981092, 14766743, 21415153, 22245519) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

DANN

Benign

0.24

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

MutationTaster

Benign

0.98

P;P;P;P

PrimateAI

Uncertain

0.69

PROVEAN

Benign

5.7

N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over