chr16-56865231-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001126108.2(SLC12A3):c.-5C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000094 ( 0 hom. )
Consequence
SLC12A3
NM_001126108.2 5_prime_UTR
NM_001126108.2 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.635
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.-5C>T | 5_prime_UTR_variant | 1/26 | ENST00000563236.6 | ||
SLC12A3 | NM_000339.3 | c.-5C>T | 5_prime_UTR_variant | 1/26 | |||
SLC12A3 | NM_001126107.2 | c.-5C>T | 5_prime_UTR_variant | 1/26 | |||
SLC12A3 | NM_001410896.1 | c.-5C>T | 5_prime_UTR_variant | 1/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.-5C>T | 5_prime_UTR_variant | 1/26 | 1 | NM_001126108.2 | A1 | ||
SLC12A3 | ENST00000438926.6 | c.-5C>T | 5_prime_UTR_variant | 1/26 | 1 | A1 | |||
SLC12A3 | ENST00000566786.5 | c.-5C>T | 5_prime_UTR_variant | 1/26 | 1 | P4 | |||
SLC12A3 | ENST00000262502.5 | c.-5C>T | 5_prime_UTR_variant | 1/26 | 5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000847 AC: 21AN: 248070Hom.: 0 AF XY: 0.0000817 AC XY: 11AN XY: 134576
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GnomAD4 exome AF: 0.0000938 AC: 137AN: 1461020Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 77AN XY: 726820
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at