6-147313972-C-G

Position:

• chr6-147313972-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001127715.4(STXBP5):​c.1234C>G​(p.Leu412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,603,784 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (12 hom.)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.66

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068151057).
• BP6: Variant 6-147313972-C-G is Benign according to our data. Variant chr6-147313972-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2656981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 500 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP5	NM_001127715.4	c.1234C>G	p.Leu412Val	missense_variant	12/28	ENST00000321680.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP5	ENST00000321680.11	c.1234C>G	p.Leu412Val	missense_variant	12/28	5	NM_001127715.4	A1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 500 AN: 151990 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00652

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00309 AC: 776 AN: 250884 Hom.: 4 AF XY: 0.00311 AC XY: 422 AN XY: 135622

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00689

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00304 AC: 4418 AN: 1451676 Hom.: 12 Cov.: 31 AF XY: 0.00312 AC XY: 2248 AN XY: 721476

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00112

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00733

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00329 AC: 500 AN: 152108 Hom.: 3 Cov.: 32 AF XY: 0.00303 AC XY: 225 AN XY: 74346

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00652

Gnomad4 NFE AF: 0.00586

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00482 Hom.: 6

Bravo AF: 0.00230

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00342 AC: 415

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

STXBP5: BS2 -

STXBP5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

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	0.089
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D;.
Eigen	Benign	0.015
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.086
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0040	B;B;.
Vest4		0.28
MVP		0.11
MPC		0.52
ClinPred		0.021	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.70

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: rs144099092; hg19: chr6-147635108;