9-127660064-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2

The NM_001032221.6(STXBP1):​c.281C>T​(p.Pro94Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000284 in 1,614,090 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P94P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00030 ( 4 hom. )

Consequence

STXBP1
NM_001032221.6 missense

Scores

1
10
8

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.97
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001032221.6
PP2
Missense variant in the STXBP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 79 curated benign missense variants. Gene score misZ: 4.263 (above the threshold of 3.09). Trascript score misZ: 5.8379 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.015435487).
BP6
Variant 9-127660064-C-T is Benign according to our data. Variant chr9-127660064-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 207405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STXBP1NM_003165.6 linkc.281C>T p.Pro94Leu missense_variant Exon 5 of 20 ENST00000373302.8 NP_003156.1 P61764-2
STXBP1NM_001032221.6 linkc.281C>T p.Pro94Leu missense_variant Exon 5 of 19 ENST00000373299.5 NP_001027392.1 P61764-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STXBP1ENST00000373302.8 linkc.281C>T p.Pro94Leu missense_variant Exon 5 of 20 1 NM_003165.6 ENSP00000362399.3 P61764-2
STXBP1ENST00000373299.5 linkc.281C>T p.Pro94Leu missense_variant Exon 5 of 19 1 NM_001032221.6 ENSP00000362396.2 P61764-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00290
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000537
AC:
135
AN:
251484
Hom.:
0
AF XY:
0.000728
AC XY:
99
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00382
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000298
AC:
436
AN:
1461874
Hom.:
4
Cov.:
31
AF XY:
0.000428
AC XY:
311
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00379
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000594
Gnomad4 OTH exome
AF:
0.000430
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00290
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000141
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.000593
AC:
72
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

STXBP1: PP2, BS1, BS2 -

Sep 09, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 11, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Sep 22, 2016
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1
Sep 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

STXBP1-related disorder Benign:1
Dec 28, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.21
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
.;T;T;.;T;.;T;T;T;D;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.015
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.1
.;.;.;M;.;.;.;.;.;M;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.9
.;.;.;D;.;.;.;.;.;D;.
REVEL
Uncertain
0.50
Sift
Benign
0.38
.;.;.;T;.;.;.;.;.;T;.
Sift4G
Benign
0.35
.;T;T;T;.;.;.;T;T;T;T
Polyphen
0.88, 0.91
.;.;.;P;.;.;.;.;.;P;.
Vest4
0.62, 0.62
MutPred
0.51
.;.;.;Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;.;.;Loss of loop (P = 0.0203);.;
MVP
0.47
MPC
2.2
ClinPred
0.11
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.30
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200802985; hg19: chr9-130422343; API