rs1554343985
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_003919.3(SGCE):c.826-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003919.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SGCE | NM_003919.3 | c.826-2A>G | splice_acceptor_variant, intron_variant | Intron 6 of 10 | ENST00000648936.2 | NP_003910.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1453168Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 722744
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Myoclonic dystonia 11 Pathogenic:1
This sequence change affects an acceptor splice site in intron 6 of the SGCE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SGCE are known to be pathogenic (PMID: 12821748, 15389977, 17853490, 24297365). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SGCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 448359). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided Pathogenic:1
- -
Inborn genetic diseases Uncertain:1
The c.826-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 7 of the SGCE gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing; however, the exact functional effect of the altered amino acid sequence is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same acceptor site, c.826-1G>A, has been detected in a patient with clinical features consistent with SGCE-related myoclonic dystonia (Nardocci, 2008). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at