chr16-30993491-T-C

Variant names:

• chr16-30993491-T-C
• rs12445568
• NM_052874.5:c.538-7A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00004004
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -6.07
• Publications: 72 publications found

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]

STX1B Gene-Disease associations (from GenCC):

• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• generalized epilepsy with febrile seizures plus, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052874.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX1B	NM_052874.5	MANE Select	c.538-7A>G		splice_region intron	N/A	NP_443106.1	P61266-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX1B	ENST00000215095.11	TSL:1 MANE Select	c.538-7A>G		splice_region intron	N/A	ENSP00000215095.5	P61266-1
	STX1B	ENST00000916717.1		c.538-7A>G		splice_region intron	N/A	ENSP00000586776.1
	STX1B	ENST00000565419.2	TSL:2	c.538-7A>G		splice_region intron	N/A	ENSP00000455899.1	P61266-2

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

GnomAD2 exomes AF: 0.392 AC: 98069 AN: 250472 AF XY: 0.405

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 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

African (AFR) AF: 0.382 AC: 12795 AN: 33474

American (AMR) AF: 0.412 AC: 18415 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8938 AN: 26132

East Asian (EAS) AF: 0.0866 AC: 3436 AN: 39698

South Asian (SAS) AF: 0.670 AC: 57741 AN: 86240

European-Finnish (FIN) AF: 0.367 AC: 19273 AN: 52538

Middle Eastern (MID) AF: 0.288 AC: 1664 AN: 5768

European-Non Finnish (NFE) AF: 0.371 AC: 412848 AN: 1111414

Other (OTH) AF: 0.369 AC: 22301 AN: 60356

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

African (AFR) AF: 0.380 AC: 15772 AN: 41462

American (AMR) AF: 0.383 AC: 5857 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1107 AN: 3468

East Asian (EAS) AF: 0.0990 AC: 512 AN: 5170

South Asian (SAS) AF: 0.694 AC: 3343 AN: 4820

European-Finnish (FIN) AF: 0.354 AC: 3747 AN: 10570

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25491 AN: 67958

Other (OTH) AF: 0.350 AC: 737 AN: 2108

Alfa AF: 0.369 Hom.: 19156

Bravo AF: 0.366

Asia WGS AF: 0.439 AC: 1524 AN: 3478

EpiCase AF: 0.364

EpiControl AF: 0.353

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Generalized epilepsy with febrile seizures plus, type 9 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.015
DANN	Benign	0.57
PhyloP100		-6.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12445568; hg19: chr16-31004812; COSMIC: COSV52682037; COSMIC: COSV52682037;