rs121918321
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003165.6(STXBP1):c.1162C>T(p.Arg388Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
STXBP1
NM_003165.6 stop_gained
NM_003165.6 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 4.20
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 18 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 9-127675855-C-T is Pathogenic according to our data. Variant chr9-127675855-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127675855-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STXBP1 | NM_003165.6 | c.1162C>T | p.Arg388Ter | stop_gained | 14/20 | ENST00000373302.8 | NP_003156.1 | |
STXBP1 | NM_001032221.6 | c.1162C>T | p.Arg388Ter | stop_gained | 14/19 | ENST00000373299.5 | NP_001027392.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STXBP1 | ENST00000373302.8 | c.1162C>T | p.Arg388Ter | stop_gained | 14/20 | 1 | NM_003165.6 | ENSP00000362399 | P3 | |
STXBP1 | ENST00000373299.5 | c.1162C>T | p.Arg388Ter | stop_gained | 14/19 | 1 | NM_001032221.6 | ENSP00000362396 | 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:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 4 Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 05, 2019 | This variant was identified as de novo (maternity and paternity confirmed). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Apr 19, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 11, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2018 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 16, 2022 | This sequence change creates a premature translational stop signal (p.Arg388*) in the STXBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STXBP1 are known to be pathogenic (PMID: 20887364, 26384463). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Ohtahara syndrome (PMID: 19557857, 26514728, 27184330). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6730). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35007884, 19557857, 25525159, 26865513, 27184330, 29997391, 34489640, 35851549, 31440721, 34247411, 26514728, 26384463, 20887364, 29538625) - |
Infantile epilepsy syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Apr 01, 2019 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-04-01 and interpreted as Pathogenic. Variant was initially reported on 2018-10-17 by GTR ID of laboratory name 61756. 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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
0.95
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at