rs1555863593
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020708.5(SLC12A5):c.980dup(p.Asn328GlnfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L327L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
SLC12A5
NM_020708.5 frameshift
NM_020708.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.10
Genes affected
SLC12A5 (HGNC:13818): (solute carrier family 12 member 5) K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-46041453-C-CT is Pathogenic according to our data. Variant chr20-46041453-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 475662.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A5 | NM_020708.5 | c.980dup | p.Asn328GlnfsTer5 | frameshift_variant | 8/26 | ENST00000243964.7 | |
SLC12A5 | NM_001134771.2 | c.1049dup | p.Asn351GlnfsTer5 | frameshift_variant | 8/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A5 | ENST00000243964.7 | c.980dup | p.Asn328GlnfsTer5 | frameshift_variant | 8/26 | 1 | NM_020708.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 34 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SLC12A5 are known to be pathogenic (PMID: 26333769, 27436767). This variant has not been reported in the literature in individuals with SLC12A5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn328Glnfs*5) in the SLC12A5 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Calibrated prediction
Score
Prediction
Splicing
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Calibrated prediction
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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