rs12445568

chr16-30993491-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052874.5(STX1B):c.538-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,612,364 control chromosomes in the GnomAD database, including 123,874 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11173 hom., cov: 32)
  • Exomes 𝑓: 0.38 (112701 hom.)
• Consequence: STX1B NM_052874.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004004
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.07

Genes affected

STX1B (HGNC:18539): (syntaxin 1B) The protein encoded by this gene belongs to a family of proteins thought to play a role in the exocytosis of synaptic vesicles. Vesicle exocytosis releases vesicular contents and is important to various cellular functions. For instance, the secretion of transmitters from neurons plays an important role in synaptic transmission. After exocytosis, the membrane and proteins from the vesicle are retrieved from the plasma membrane through the process of endocytosis. Mutations in this gene have been identified as one cause of fever-associated epilepsy syndromes. A possible link between this gene and Parkinson's disease has also been suggested. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-30993491-T-C is Benign according to our data. Variant chr16-30993491-T-C is described in ClinVar as [Benign]. Clinvar id is 586685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX1B	NM_052874.5	c.538-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000215095.11
STX1B	XM_017022893.2	c.520-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX1B	ENST00000215095.11	c.538-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_052874.5	P1
STX1B	ENST00000565419.2	c.538-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56918 AN: 151916 Hom.: 11162 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.0994

Gnomad SAS AF: 0.695

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.392 AC: 98069 AN: 250472 Hom.: 21563 AF XY: 0.405 AC XY: 54820 AN XY: 135412

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.0934

Gnomad SAS exome AF: 0.678

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.365

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.382 AC: 557411 AN: 1460330 Hom.: 112701 Cov.: 44 AF XY: 0.389 AC XY: 282847 AN XY: 726434

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.412

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.0866

Gnomad4 SAS exome AF: 0.670

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.375 AC: 56951 AN: 152034 Hom.: 11173 Cov.: 32 AF XY: 0.376 AC XY: 27978 AN XY: 74312

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.0990

Gnomad4 SAS AF: 0.694

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.350

Alfa AF: 0.372 Hom.: 14972

Bravo AF: 0.366

Asia WGS AF: 0.439 AC: 1524 AN: 3478

EpiCase AF: 0.364

EpiControl AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Generalized epilepsy with febrile seizures plus, type 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.015
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs12445568; hg19: chr16-31004812; COSMIC: COSV52682037; COSMIC: COSV52682037;