rs754378340
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001126108.2(SLC12A3):c.2533del(p.Leu845SerfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,060 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. L844L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001126108.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.2533del | p.Leu845SerfsTer21 | frameshift_variant | 22/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.2560del | p.Leu854SerfsTer21 | frameshift_variant | 22/26 | ||
SLC12A3 | NM_001126107.2 | c.2557del | p.Leu853SerfsTer21 | frameshift_variant | 22/26 | ||
SLC12A3 | NM_001410896.1 | c.2530del | p.Leu844SerfsTer21 | frameshift_variant | 22/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.2533del | p.Leu845SerfsTer21 | frameshift_variant | 22/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.2560del | p.Leu854SerfsTer21 | frameshift_variant | 22/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.2557del | p.Leu853SerfsTer21 | frameshift_variant | 22/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.2530del | p.Leu844SerfsTer21 | frameshift_variant | 22/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250264Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135222
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461060Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726748
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 02, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 18, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2023 | This variant is present in population databases (rs754378340, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 586604). This premature translational stop signal has been observed in individual(s) with Gitelman syndrome (PMID: 25422309). This sequence change creates a premature translational stop signal (p.Leu854Serfs*21) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 06, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2021 | The c.2560delC (p.L854Sfs*21) alteration, located in coding exon 22 of the SLC12A3 gene, consists of a deletion of one nucleotide at position 2560, causing a translational frameshift with a predicted alternate stop codon after 21 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration was reported to occur with a second splice site alteration in a male patient diagnosed with Gitelman syndrome (Corbetta, 2015). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at