chr16-30993375-A-T

Variant names:

• chr16-30993375-A-T
• rs724159974
• NM_052874.5:c.647T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_052874.5(STX1B):​c.647T>A​(p.Val216Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STX1B NM_052874.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95
• Publications: 7 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: Orphanet, ClinGen
• generalized epilepsy with febrile seizures plus, type 9

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• PP5: Variant 16-30993375-A-T is Pathogenic according to our data. Variant chr16-30993375-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 162398.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.647T>A	p.Val216Glu	missense_variant	Exon 8 of 10	ENST00000215095.11	NP_443106.1
STX1B	XM_017022893.2	c.629T>A	p.Val210Glu	missense_variant	Exon 8 of 10		XP_016878382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STX1B	ENST00000215095.11	c.647T>A	p.Val216Glu	missense_variant	Exon 8 of 10	1	NM_052874.5	ENSP00000215095.5
STX1B	ENST00000565419.2	c.647T>A	p.Val216Glu	missense_variant	Exon 8 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	0.87
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		8.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.079	B;.
Vest4		0.89
MutPred		0.58		Loss of catalytic residue at V216 (P = 0.0058);Loss of catalytic residue at V216 (P = 0.0058);
MVP		0.70
MPC		2.0
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs724159974; hg19: chr16-31004696;