chr16-56865278-TTG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001126108.2(SLC12A3):​c.46_47del​(p.Cys16GlnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.46
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 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 345 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-56865278-TTG-T is Pathogenic according to our data. Variant chr16-56865278-TTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1459093.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC12A3NM_001126108.2 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/26 ENST00000563236.6
SLC12A3NM_000339.3 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/26
SLC12A3NM_001126107.2 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/26
SLC12A3NM_001410896.1 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/26

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC12A3ENST00000563236.6 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/261 NM_001126108.2 A1P55017-1
SLC12A3ENST00000438926.6 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/261 A1P55017-2
SLC12A3ENST00000566786.5 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/261 P4P55017-3
SLC12A3ENST00000262502.5 linkuse as main transcriptc.46_47del p.Cys16GlnfsTer13 frameshift_variant 1/265 A1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250758
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
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:
1
AN:
1461580
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
727112
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 07, 2023This sequence change creates a premature translational stop signal (p.Cys16Glnfs*13) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Gitelman syndrome (PMID: 8900229). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs1567423490; hg19: chr16-56899190; API