16-56869780-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001126108.2(SLC12A3):​c.557G>C​(p.Gly186Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

4
4
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC12A3NM_001126108.2 linkc.557G>C p.Gly186Ala missense_variant Exon 4 of 26 ENST00000563236.6 NP_001119580.2 P55017-1
SLC12A3NM_000339.3 linkc.557G>C p.Gly186Ala missense_variant Exon 4 of 26 NP_000330.3 P55017-2
SLC12A3NM_001126107.2 linkc.554G>C p.Gly185Ala missense_variant Exon 4 of 26 NP_001119579.2 P55017-3
SLC12A3NM_001410896.1 linkc.554G>C p.Gly185Ala missense_variant Exon 4 of 26 NP_001397825.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC12A3ENST00000563236.6 linkc.557G>C p.Gly186Ala missense_variant Exon 4 of 26 1 NM_001126108.2 ENSP00000456149.2 P55017-1
SLC12A3ENST00000438926.6 linkc.557G>C p.Gly186Ala missense_variant Exon 4 of 26 1 ENSP00000402152.2 P55017-2
SLC12A3ENST00000566786.5 linkc.554G>C p.Gly185Ala missense_variant Exon 4 of 26 1 ENSP00000457552.1 P55017-3
SLC12A3ENST00000262502.5 linkc.554G>C p.Gly185Ala missense_variant Exon 4 of 26 5 ENSP00000262502.5 J3QSS1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251386
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135870
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727222
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
26
DANN
Benign
0.93
DEOGEN2
Pathogenic
0.88
.;.;D;D
Eigen
Benign
0.048
Eigen_PC
Benign
0.20
FATHMM_MKL
Benign
0.57
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.77
D;D;D;D
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.040
.;N;N;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-2.9
D;D;D;D
REVEL
Uncertain
0.36
Sift
Benign
0.45
T;T;T;T
Sift4G
Benign
0.54
T;T;T;T
Polyphen
0.075
B;P;P;.
Vest4
0.88
MutPred
0.65
.;Loss of catalytic residue at L187 (P = 0.0919);Loss of catalytic residue at L187 (P = 0.0919);.;
MVP
0.98
MPC
0.12
ClinPred
0.53
D
GERP RS
4.9
Varity_R
0.48
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs759426055; hg19: chr16-56903692; API