NM_000100.4:c.202C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000100.4(CSTB):c.202C>T(p.Arg68*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000100.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251462Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135920
GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727222
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
Unverricht-Lundborg syndrome Pathogenic:3Other:1
The CSTB c.202C>T (p.Arg68Ter) variant has been reported in over 10 patients with Unverricht-Lundborg syndrome and is reported to segregate with disease in six individuals in three families (Koskenkorva P et al., PMID: 21757863; Lafreniere RG et al., PMID: 9054946; Mancini GM et al., PMID: 26843564, Pennacchio LA et al., PMID: 8596935). Of those individuals, two siblings were homozygous for the variant (Mancini GM et al., PMID: 26843564) and seven were compound heterozygous for the variant and a pathogenic repeat expansion confirmed in trans (Koskenkorva P et al., PMID: 21757863). This variant leads to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. It does disrupt the last 31 amino acids of the CSTB protein. Functional studies show protein aggregation in the perinuclear region and reduced cell viability compared to wild type, indicating that this variant impacts protein function (Ceru S et al., PMID: 20078424; Rabzelj S et al., PMID: 16155205). This variant is only observed on 13 out of 282,868 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a germline pathogenic variant by five submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
- -
The c.202C>T (p.Arg68Ter) variant has been reported in at least five studies in which it is found in a total of 11 Unverricht-Lundborg disease patients, including two affected siblings in a homozygous state, seven patients in a compound heterozygous state (including two sibling pairs), and in two patient alleles where zygosity was not specified (Pennacchio et al. 1996; Lafrenière et al. 1997; de Haan et al. 2004; Koskenkorva et al. 2010; Mancini et al. 2016). The p.Arg68Ter variant was absent from 377 controls but is reported at a frequency of 0.00006 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional analyses demonstrated that the variant resulted in reduced cell viability by 26% compared to wild-type in transfected CHO-K1 cells (Ceru et al. 2010). Additionally, the p.Arg68Ter variant protein did not localize to the nucleus. The variant produced an unfolded protein leading to protein aggregation which resulted in perinuclear aggregates that were more pronounced than wild type (Rabzelj et al. 2005; Ceru et al. 2010; Polajnar et al. 2012). Based on the evidence and the potential impact of stop-gained variants, the p.Arg68Ter variant is classified as pathogenic for Unverricht-Lundborg disease. -
- -
Self-limited epilepsy with centrotemporal spikes Pathogenic:1
CAADphred>15 -
not provided Pathogenic:1
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with progressive myoclonic epilepsy. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant leads to the formation of protein aggregates (PMID: 17920138, 20078424) -
Dyskinesia;C0013421:Dystonic disorder;C0036857:Intellectual disability, severe;C0241816:Global brain atrophy;C1837397:Severe global developmental delay;C1850456:Progressive microcephaly;C1854301:Motor delay;C1861866:Aplasia/Hypoplasia of the corpus callosum Pathogenic:1
- -
Progressive myoclonic epilepsy Pathogenic:1
Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CSTB protein in which other variant(s) (p.Leu73Profs*3) have been determined to be pathogenic (PMID: 9054946, 9342192, 15483648, 17920138). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this premature translational stop signal affects CSTB function (PMID: 15483648). ClinVar contains an entry for this variant (Variation ID: 8396). This premature translational stop signal has been observed in individual(s) with progressive myoclonus epilepsy (PMID: 8596935, 26843564). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315442, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg68*) in the CSTB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the CSTB protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at