rs727502806

Variant names:

• chr16-30993240-C-G
• rs727502806
• NM_052874.5:c.676G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_052874.5(STX1B):​c.676G>C​(p.Gly226Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STX1B NM_052874.5 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.84

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 16-30993240-C-G is Pathogenic according to our data. Variant chr16-30993240-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 162399.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX1B	NM_052874.5	c.676G>C	p.Gly226Arg	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000215095.11	NP_443106.1
STX1B	XM_017022893.2	c.658G>C	p.Gly220Arg	missense_variant, splice_region_variant	Exon 9 of 10		XP_016878382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STX1B	ENST00000215095.11	c.676G>C	p.Gly226Arg	missense_variant, splice_region_variant	Exon 9 of 10	1	NM_052874.5	ENSP00000215095.5
STX1B	ENST00000565419.2	c.676G>C	p.Gly226Arg	missense_variant, splice_region_variant	Exon 9 of 9	2		ENSP00000455899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 9 Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Pathogenic	3.9	H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.79		Loss of catalytic residue at Q225 (P = 0.0614);Loss of catalytic residue at Q225 (P = 0.0614);
MVP		0.68
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
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: rs727502806; hg19: chr16-31004561;