chr6-147262345-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001127715.4(STXBP5):​c.622G>A​(p.Glu208Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,561,912 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: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

STXBP5
NM_001127715.4 missense

Scores

7
4
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
STXBP5 (HGNC:19665): (syntaxin binding protein 5) Syntaxin 1 is a component of the 7S and 20S SNARE complexes which are involved in docking and fusion of synaptic vesicles with the presynaptic plasma membrane. This gene encodes a syntaxin 1 binding protein. In rat, a similar protein dissociates syntaxin 1 from the Munc18/n-Sec1/rbSec1 complex to form a 10S complex, an intermediate which can be converted to the 7S SNARE complex. Thus this protein is thought to be involved in neurotransmitter release by stimulating SNARE complex formation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.39062765).
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STXBP5NM_001127715.4 linkuse as main transcriptc.622G>A p.Glu208Lys missense_variant 6/28 ENST00000321680.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STXBP5ENST00000321680.11 linkuse as main transcriptc.622G>A p.Glu208Lys missense_variant 6/285 NM_001127715.4 A1Q5T5C0-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
151814
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000516
AC:
11
AN:
212980
Hom.:
0
AF XY:
0.0000515
AC XY:
6
AN XY:
116430
show subpopulations
Gnomad AFR exome
AF:
0.000651
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000846
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000163
AC:
23
AN:
1409982
Hom.:
0
Cov.:
27
AF XY:
0.0000171
AC XY:
12
AN XY:
700478
show subpopulations
Gnomad4 AFR exome
AF:
0.000357
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000265
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000825
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
151930
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000167
Hom.:
0
Bravo
AF:
0.000125
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000743
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2021The c.622G>A (p.E208K) alteration is located in exon 6 (coding exon 6) of the STXBP5 gene. This alteration results from a G to A substitution at nucleotide position 622, causing the glutamic acid (E) at amino acid position 208 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Uncertain
0.054
T
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.025
T;.;T;.
Eigen
Uncertain
0.65
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Benign
0.075
D
MetaRNN
Benign
0.39
T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
2.0
.;M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-2.2
N;N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.42
T;T;T;T
Sift4G
Uncertain
0.046
D;T;T;T
Polyphen
1.0, 1.0
.;D;D;.
Vest4
0.88
MVP
0.46
MPC
0.66
ClinPred
0.19
T
GERP RS
5.2
Varity_R
0.36
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs367614502; hg19: chr6-147583481; COSMIC: COSV51651586; API