rs748965227
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP6BS2
The NM_003165.6(STXBP1):c.1256C>T(p.Thr419Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T419T) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
STXBP1
NM_003165.6 missense
NM_003165.6 missense
Scores
6
6
1
Clinical Significance
Conservation
PhyloP100: 5.75
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 1 benign, 3 uncertain in NM_003165.6
PP2
?
Missense variant where missense usually causes diseases, STXBP1
BP6
?
Variant 9-127676650-C-T is Benign according to our data. Variant chr9-127676650-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207434.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
?
High AC in GnomAdExome4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP1 | NM_003165.6 | c.1256C>T | p.Thr419Met | missense_variant | 15/20 | ENST00000373302.8 | |
STXBP1 | NM_001032221.6 | c.1256C>T | p.Thr419Met | missense_variant | 15/19 | ENST00000373299.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP1 | ENST00000373302.8 | c.1256C>T | p.Thr419Met | missense_variant | 15/20 | 1 | NM_003165.6 | P3 | |
STXBP1 | ENST00000373299.5 | c.1256C>T | p.Thr419Met | missense_variant | 15/19 | 1 | NM_001032221.6 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250740Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135558
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727028
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2013 | p.Thr419Met (ACG>ATG): c.1256 C>T in exon 15 of the STXBP1 gene (NM_003165.2)The Thr419Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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. This variant is a non-conservative amino acid substitution of a polar Threonine residue with a non-polar Methionine residue at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. This variant has been observede to be maternally inherited from an apparently unaffected mother; The variant is found in EPILEPSY panel(s). - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Polyphen
1.0
.;.;D;.;.;.;D
Vest4
0.79, 0.79
MutPred
0.42
.;.;Loss of methylation at K415 (P = 0.1021);Loss of methylation at K415 (P = 0.1021);Loss of methylation at K415 (P = 0.1021);.;Loss of methylation at K415 (P = 0.1021);
MVP
0.70
MPC
2.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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