6-147315617-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001127715.4(STXBP5):c.1505A>G(p.Tyr502Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00458 in 1,613,960 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (17 hom.)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.46

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009953707).
• BP6: Variant 6-147315617-A-G is Benign according to our data. Variant chr6-147315617-A-G is described in ClinVar as [Benign]. Clinvar id is 779426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 560 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP5	NM_001127715.4	c.1505A>G	p.Tyr502Cys	missense_variant	15/28	ENST00000321680.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP5	ENST00000321680.11	c.1505A>G	p.Tyr502Cys	missense_variant	15/28	5	NM_001127715.4	A1

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00395 AC: 991 AN: 251122 Hom.: 5 AF XY: 0.00411 AC XY: 558 AN XY: 135726

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00468 AC: 6837 AN: 1461632 Hom.: 17 Cov.: 31 AF XY: 0.00461 AC XY: 3350 AN XY: 727124

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00827

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.00330

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00375 AC XY: 279 AN XY: 74482

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00501 Hom.: 7

Bravo AF: 0.00271

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00364 AC: 442

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 17, 2018

- -

STXBP5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2021

This variant is classified as 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	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.070
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.90	P;P;.
Vest4		0.56
MVP		0.068
MPC		0.63
ClinPred		0.075	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.89

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

Other links and lift over

dbSNP: rs148830578; hg19: chr6-147636753; COSMIC: COSV51654315;