chr9-127612424-A-AGCTGTTGTCGG

Position:

• chr9-127612424-A-AGCTGTTGTCGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003165.6(STXBP1):​c.22_32dup​(p.Glu12LeufsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_003165.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.64

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 281 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127612424-A-AGCTGTTGTCGG is Pathogenic according to our data. Variant chr9-127612424-A-AGCTGTTGTCGG is described in ClinVar as [Pathogenic]. Clinvar id is 572405.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_001032221.6	c.22_32dup	p.Glu12LeufsTer11	frameshift_variant	1/19	ENST00000373299.5
STXBP1	NM_003165.6	c.22_32dup	p.Glu12LeufsTer11	frameshift_variant	1/20	ENST00000373302.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373299.5	c.22_32dup	p.Glu12LeufsTer11	frameshift_variant	1/19	1	NM_001032221.6	A1
STXBP1	ENST00000373302.8	c.22_32dup	p.Glu12LeufsTer11	frameshift_variant	1/20	1	NM_003165.6	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in STXBP1 are known to be pathogenic (PMID: 20887364, 26384463). This variant has not been reported in the literature in individuals with STXBP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu12Leufs*11) in the STXBP1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1564333757; hg19: chr9-130374703;