Variant chr16-56865236-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_001126108.2(SLC12A3):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,224 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.36

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 Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_001126108.2 (SLC12A3) was described as [Pathogenic] in ClinVar as 945564

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56865236-A-G is Pathogenic according to our data. Variant chr16-56865236-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1684155.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.1A>G	p.Met1?	start_lost	1/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/26	5		A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248774

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

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:

1461224

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP

Apr 27, 2022

ACMG criteria used: PVS1, PS1, PM1, PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;.;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.66

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Benign

-0.66

N;N;N;N

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.076

T;T;T;T

Polyphen

0.99

D;D;P;.

Vest4

0.97

MutPred

0.96

Loss of solvent accessibility (P = 0.1301);Loss of solvent accessibility (P = 0.1301);Loss of solvent accessibility (P = 0.1301);Loss of solvent accessibility (P = 0.1301);

MVP

0.95

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

gMVP

0.76

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