16-56865290-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The NM_001126108.2(SLC12A3):c.55C>T(p.Arg19Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.26

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 134) in uniprot entity S12A3_HUMAN there are 22 pathogenic changes around while only 6 benign (79%) in NM_001126108.2

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56865290-C-T is Pathogenic according to our data. Variant chr16-56865290-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813955.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	1/26	5		A1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250904

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461628

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The heterozygous p.Arg19Cys variant in SLC12A3 was identified by our study in the compound heterozygous state, with a VUS, in one individual with Gitelman syndrome. Trio exome analysis showed this variant to be de novo. This variant has been identified in 0.01191% (4/33578) of Latino chromosomes chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374055486). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg19Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS2 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.16

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

0.0

N;N;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

D;D;D;D

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.67

MVP

0.93

MPC

0.55

ClinPred

0.69

GERP RS

5.3

Varity_R

0.29

gMVP

0.70

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