rs756942804
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001365999.1(SZT2):c.654_655del(p.Asp220ProfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,597,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
SZT2
NM_001365999.1 frameshift
NM_001365999.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.53
Genes affected
SZT2 (HGNC:29040): (SZT2 subunit of KICSTOR complex) The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]
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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 1-43415982-CAG-C is Pathogenic according to our data. Variant chr1-43415982-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436935.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SZT2 | NM_001365999.1 | c.654_655del | p.Asp220ProfsTer14 | frameshift_variant | 6/72 | ENST00000634258.3 | |
SZT2 | NM_015284.4 | c.654_655del | p.Asp220ProfsTer14 | frameshift_variant | 6/71 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SZT2 | ENST00000634258.3 | c.654_655del | p.Asp220ProfsTer14 | frameshift_variant | 6/72 | 5 | NM_001365999.1 | P1 | |
SZT2 | ENST00000562955.2 | c.654_655del | p.Asp220ProfsTer14 | frameshift_variant | 6/71 | 5 | |||
SZT2 | ENST00000639852.1 | c.303_304del | p.Asp103ProfsTer14 | frameshift_variant, NMD_transcript_variant | 3/9 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000176 AC: 4AN: 227688Hom.: 0 AF XY: 0.0000238 AC XY: 3AN XY: 125896
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GnomAD4 exome AF: 0.0000125 AC: 18AN: 1445600Hom.: 0 AF XY: 0.0000181 AC XY: 13AN XY: 719488
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 18 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 25, 2017 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at