16-56879153-T-G
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001126108.2(SLC12A3):c.1261T>G(p.Cys421Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
SLC12A3
NM_001126108.2 missense
NM_001126108.2 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.88
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946
PP5
Variant 16-56879153-T-G is Pathogenic according to our data. Variant chr16-56879153-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1256468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.1261T>G | p.Cys421Gly | missense_variant | 10/26 | ENST00000563236.6 | NP_001119580.2 | |
SLC12A3 | NM_000339.3 | c.1261T>G | p.Cys421Gly | missense_variant | 10/26 | NP_000330.3 | ||
SLC12A3 | NM_001126107.2 | c.1258T>G | p.Cys420Gly | missense_variant | 10/26 | NP_001119579.2 | ||
SLC12A3 | NM_001410896.1 | c.1258T>G | p.Cys420Gly | missense_variant | 10/26 | NP_001397825.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.1261T>G | p.Cys421Gly | missense_variant | 10/26 | 1 | NM_001126108.2 | ENSP00000456149.2 | ||
SLC12A3 | ENST00000438926.6 | c.1261T>G | p.Cys421Gly | missense_variant | 10/26 | 1 | ENSP00000402152.2 | |||
SLC12A3 | ENST00000566786.5 | c.1258T>G | p.Cys420Gly | missense_variant | 10/26 | 1 | ENSP00000457552.1 | |||
SLC12A3 | ENST00000262502.5 | c.1258T>G | p.Cys420Gly | missense_variant | 10/26 | 5 | ENSP00000262502.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 14, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 18, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;H;H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;.
Vest4
MutPred
0.67
.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP
MPC
0.51
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.