rs1348662627
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4BS2
The NM_003165.6(STXBP1):c.628G>A(p.Asp210Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
STXBP1
NM_003165.6 missense
NM_003165.6 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 6.40
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 Likely_benign. Variant got -2 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003165.6
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STXBP1. . Gene score misZ 4.263 (greater than the threshold 3.09). Trascript score misZ 5.8329 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.
BP4
Computational evidence support a benign effect (MetaRNN=0.39183253).
BS2
High AC in GnomAdExome4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP1 | NM_003165.6 | c.628G>A | p.Asp210Asn | missense_variant | 8/20 | ENST00000373302.8 | |
STXBP1 | NM_001032221.6 | c.628G>A | p.Asp210Asn | missense_variant | 8/19 | ENST00000373299.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP1 | ENST00000373302.8 | c.628G>A | p.Asp210Asn | missense_variant | 8/20 | 1 | NM_003165.6 | P3 | |
STXBP1 | ENST00000373299.5 | c.628G>A | p.Asp210Asn | missense_variant | 8/19 | 1 | NM_001032221.6 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251478Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727246
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2017 | This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with STXBP1-related disease. This sequence change replaces aspartic acid with asparagine at codon 210 of the STXBP1 protein (p.Asp210Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | STXBP1: PP2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.;T;D
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;L;.;.;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;N;.;.;.;N
REVEL
Uncertain
Sift
Benign
.;.;T;.;.;.;T
Sift4G
Benign
.;.;T;.;.;.;T
Polyphen
0.73, 0.77
.;.;P;.;.;.;P
Vest4
0.23, 0.23
MutPred
0.56
.;.;Loss of phosphorylation at Y212 (P = 0.079);Loss of phosphorylation at Y212 (P = 0.079);Loss of phosphorylation at Y212 (P = 0.079);.;Loss of phosphorylation at Y212 (P = 0.079);
MVP
0.85
MPC
1.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at