chr16-56865286-C-A

Position:

chr16-56865286-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001126108.2(SLC12A3):c.51C>A(p.Ser17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S17S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -2.80

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001126108.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09460428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.51C>A	p.Ser17Arg	missense_variant	1/26	5		A1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250856

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000177

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000649

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000126

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2021

The c.51C>A (p.S17R) alteration is located in exon 1 (coding exon 1) of the SLC12A3 gene. This alteration results from a C to A substitution at nucleotide position 51, causing the serine (S) at amino acid position 17 to be replaced by an arginine (R). The p.S17R alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 17 of the SLC12A3 protein (p.Ser17Arg). This variant is present in population databases (rs369795019, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SLC12A3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC12A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.20

CADD

Benign

0.15

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.74

T;T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.095

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.0

N;N;N;.

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.66

N;N;N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.019

D;D;D;D

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.99

D;D;D;.

Vest4

0.34

MutPred

0.21

Gain of methylation at S17 (P = 0.0189);Gain of methylation at S17 (P = 0.0189);Gain of methylation at S17 (P = 0.0189);Gain of methylation at S17 (P = 0.0189);

MVP

0.60

MPC

0.10

ClinPred

0.19

GERP RS

-6.4

Varity_R

0.39

gMVP

0.57

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