chr6-147267084-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001127715.4(STXBP5):ā€‹c.631C>Gā€‹(p.Leu211Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,607,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000027 ( 0 hom. )

Consequence

STXBP5
NM_001127715.4 missense, splice_region

Scores

1
10
8
Splicing: ADA: 0.9591
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STXBP5NM_001127715.4 linkuse as main transcriptc.631C>G p.Leu211Val missense_variant, splice_region_variant 7/28 ENST00000321680.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STXBP5ENST00000321680.11 linkuse as main transcriptc.631C>G p.Leu211Val missense_variant, splice_region_variant 7/285 NM_001127715.4 A1Q5T5C0-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152054
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000325
AC:
8
AN:
245860
Hom.:
0
AF XY:
0.0000377
AC XY:
5
AN XY:
132768
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000912
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000445
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000275
AC:
40
AN:
1455484
Hom.:
0
Cov.:
30
AF XY:
0.0000290
AC XY:
21
AN XY:
723820
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000931
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152054
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

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 GeneticsJan 18, 2023The c.631C>G (p.L211V) alteration is located in exon 7 (coding exon 7) of the STXBP5 gene. This alteration results from a C to G substitution at nucleotide position 631, causing the leucine (L) at amino acid position 211 to be replaced by a valine (V). 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
Benign
0.28
BayesDel_addAF
Uncertain
0.044
T
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.;T;.
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Benign
0.073
D
MetaRNN
Uncertain
0.68
D;D;D;D
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.3
.;L;L;L
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.5
N;N;N;N
REVEL
Benign
0.13
Sift
Uncertain
0.010
D;D;D;D
Sift4G
Benign
0.062
T;T;T;T
Polyphen
0.037, 0.028
.;B;B;.
Vest4
0.87
MutPred
0.54
Gain of methylation at K210 (P = 0.031);Gain of methylation at K210 (P = 0.031);Gain of methylation at K210 (P = 0.031);Gain of methylation at K210 (P = 0.031);
MVP
0.55
MPC
0.53
ClinPred
0.18
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.96
dbscSNV1_RF
Benign
0.70
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: rs765084169; hg19: chr6-147588220; API