16-56879153-T-G

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

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.88
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]

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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
SLC12A3NM_001126108.2 linkc.1261T>G p.Cys421Gly missense_variant 10/26 ENST00000563236.6 NP_001119580.2 P55017-1
SLC12A3NM_000339.3 linkc.1261T>G p.Cys421Gly missense_variant 10/26 NP_000330.3 P55017-2
SLC12A3NM_001126107.2 linkc.1258T>G p.Cys420Gly missense_variant 10/26 NP_001119579.2 P55017-3
SLC12A3NM_001410896.1 linkc.1258T>G p.Cys420Gly missense_variant 10/26 NP_001397825.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC12A3ENST00000563236.6 linkc.1261T>G p.Cys421Gly missense_variant 10/261 NM_001126108.2 ENSP00000456149.2 P55017-1
SLC12A3ENST00000438926.6 linkc.1261T>G p.Cys421Gly missense_variant 10/261 ENSP00000402152.2 P55017-2
SLC12A3ENST00000566786.5 linkc.1258T>G p.Cys420Gly missense_variant 10/261 ENSP00000457552.1 P55017-3
SLC12A3ENST00000262502.5 linkc.1258T>G p.Cys420Gly missense_variant 10/265 ENSP00000262502.5 J3QSS1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 14, 2022- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMay 18, 2021This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
.;.;D;D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Uncertain
0.070
D
MutationAssessor
Pathogenic
3.5
.;H;H;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-11
D;D;D;D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.97
MutPred
0.67
.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP
0.94
MPC
0.51
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.87
gMVP
0.89

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: chr16-56913065; API