rs1555501437

Variant summary

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

The NM_001126108.2(SLC12A3):​c.2495A>C​(p.Asp832Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 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

11
7
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.17
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC12A3NM_001126108.2 linkc.2495A>C p.Asp832Ala missense_variant Exon 21 of 26 ENST00000563236.6 NP_001119580.2 P55017-1
SLC12A3NM_000339.3 linkc.2522A>C p.Asp841Ala missense_variant Exon 21 of 26 NP_000330.3 P55017-2
SLC12A3NM_001126107.2 linkc.2519A>C p.Asp840Ala missense_variant Exon 21 of 26 NP_001119579.2 P55017-3
SLC12A3NM_001410896.1 linkc.2492A>C p.Asp831Ala missense_variant Exon 21 of 26 NP_001397825.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC12A3ENST00000563236.6 linkc.2495A>C p.Asp832Ala missense_variant Exon 21 of 26 1 NM_001126108.2 ENSP00000456149.2 P55017-1
SLC12A3ENST00000438926.6 linkc.2522A>C p.Asp841Ala missense_variant Exon 21 of 26 1 ENSP00000402152.2 P55017-2
SLC12A3ENST00000566786.5 linkc.2519A>C p.Asp840Ala missense_variant Exon 21 of 26 1 ENSP00000457552.1 P55017-3
SLC12A3ENST00000262502.5 linkc.2492A>C p.Asp831Ala missense_variant Exon 21 of 26 5 ENSP00000262502.5 J3QSS1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461796
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727208
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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
.;.;D;D
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Pathogenic
3.4
.;.;M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-7.2
D;D;D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.97
MutPred
0.64
.;.;Loss of ubiquitination at K829 (P = 0.0561);.;
MVP
0.98
MPC
0.52
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.94
gMVP
0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56926940; API