Variant 16-56884085-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001126108.2(SLC12A3):c.1706C>A(p.Ala569Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A569V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.1706C>A	p.Ala569Glu	missense_variant	14/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.1706C>A	p.Ala569Glu	missense_variant	14/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.1703C>A	p.Ala568Glu	missense_variant	14/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.1703C>A	p.Ala568Glu	missense_variant	14/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.1706C>A	p.Ala569Glu	missense_variant	14/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.1706C>A	p.Ala569Glu	missense_variant	14/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.1703C>A	p.Ala568Glu	missense_variant	14/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.1703C>A	p.Ala568Glu	missense_variant	14/26	5		A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251174

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.87

.;.;D;D

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.7

.;L;L;.

MutationTaster

Benign

0.89

N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.012

D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D

Polyphen

0.052

B;B;B;.

Vest4

0.74

MutPred

0.82

.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;

MVP

0.95

MPC

0.12

ClinPred

0.53

GERP RS

3.6

Varity_R

0.32

gMVP

0.96

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