chr9-127668188-G-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_003165.6(STXBP1):c.902+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
STXBP1
NM_003165.6 splice_donor
NM_003165.6 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.91
Genes affected
STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.059050772 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 9-127668188-G-C is Pathogenic according to our data. Variant chr9-127668188-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 280844.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP1 | NM_001032221.6 | c.902+1G>C | splice_donor_variant | ENST00000373299.5 | |||
STXBP1 | NM_003165.6 | c.902+1G>C | splice_donor_variant | ENST00000373302.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP1 | ENST00000373299.5 | c.902+1G>C | splice_donor_variant | 1 | NM_001032221.6 | A1 | |||
STXBP1 | ENST00000373302.8 | c.902+1G>C | splice_donor_variant | 1 | NM_003165.6 | P3 |
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:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2016 | The c.902+1G>C pathogenic variant in the STXBP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a different nucleotide substitution at the same position (c.902+1G>A) has been reported previously in two individuals with Ohtahara syndrome (Milh et al., 2011; Kodera et al., 2013). The c.902+1G>C splice site variant destroys the canonical splice donor site in intron 10, which is predicted to cause abnormal gene splicing. The c.902+1G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.902+1G>C as a pathogenic variant - |
Infantile epilepsy syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Mar 26, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-03-26 and interpreted as Pathogenic. Variant was initially reported on 2016-09-19 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -9
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at