6-147359223-A-G

Variant names:

• chr6-147359223-A-G
• rs9390459
• NM_001127715.4:c.2445A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP7 BA1

The NM_001127715.4(STXBP5):​c.2445A>G​(p.Leu815Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,613,772 control chromosomes in the GnomAD database, including 251,496 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (23202 hom., cov: 32)
  • Exomes 𝑓: 0.56 (228294 hom.)
• Consequence: STXBP5 NM_001127715.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• Publications: 45 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP7: Synonymous conserved (PhyloP=-0.093 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127715.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5	NM_001127715.4	MANE Select	c.2445A>G	p.Leu815Leu	synonymous	Exon 23 of 28	NP_001121187.1
	STXBP5	NM_001394409.1		c.2397A>G	p.Leu799Leu	synonymous	Exon 22 of 27	NP_001381338.1
	STXBP5	NM_139244.6		c.2337A>G	p.Leu779Leu	synonymous	Exon 21 of 26	NP_640337.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5	ENST00000321680.11	TSL:5 MANE Select	c.2445A>G	p.Leu815Leu	synonymous	Exon 23 of 28	ENSP00000321826.6
	STXBP5	ENST00000367481.7	TSL:1	c.2337A>G	p.Leu779Leu	synonymous	Exon 21 of 26	ENSP00000356451.3
	STXBP5	ENST00000443556.2	TSL:1	n.2786A>G		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83514 AN: 151938 Hom.: 23192 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.530 AC: 133264 AN: 251250 AF XY: 0.531

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.273

Gnomad FIN exome AF: 0.504

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.556 AC: 813023 AN: 1461716 Hom.: 228294 Cov.: 63 AF XY: 0.555 AC XY: 403582 AN XY: 727170

African (AFR) AF: 0.582 AC: 19467 AN: 33466

American (AMR) AF: 0.554 AC: 24750 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14544 AN: 26132

East Asian (EAS) AF: 0.274 AC: 10888 AN: 39694

South Asian (SAS) AF: 0.532 AC: 45930 AN: 86254

European-Finnish (FIN) AF: 0.511 AC: 27320 AN: 53418

Middle Eastern (MID) AF: 0.579 AC: 3337 AN: 5764

European-Non Finnish (NFE) AF: 0.570 AC: 633999 AN: 1111900

Other (OTH) AF: 0.543 AC: 32788 AN: 60390

GnomAD4 genome AF: 0.550 AC: 83566 AN: 152056 Hom.: 23202 Cov.: 32 AF XY: 0.544 AC XY: 40430 AN XY: 74324

African (AFR) AF: 0.580 AC: 24056 AN: 41488

American (AMR) AF: 0.560 AC: 8545 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1925 AN: 3466

East Asian (EAS) AF: 0.275 AC: 1418 AN: 5150

South Asian (SAS) AF: 0.524 AC: 2527 AN: 4820

European-Finnish (FIN) AF: 0.505 AC: 5327 AN: 10556

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 37982 AN: 67992

Other (OTH) AF: 0.555 AC: 1170 AN: 2110

Alfa AF: 0.556 Hom.: 110538

Bravo AF: 0.555

Asia WGS AF: 0.432 AC: 1501 AN: 3478

EpiCase AF: 0.567

EpiControl AF: 0.574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.3
DANN	Benign	0.40
PhyloP100		-0.093
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9390459; hg19: chr6-147680359; COSMIC: COSV51649341;