9-127690797-AC-A

Position:

• chr9-127690797-AC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001032221.6(STXBP1):​c.1726delC​(p.Gln576fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.60

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]

PTRH1 (HGNC:27039): (peptidyl-tRNA hydrolase 1 homolog) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000279571 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0331 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127690797-AC-A is Pathogenic according to our data. Variant chr9-127690797-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 207462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_001032221.6	c.1726delC	p.Gln576fs	frameshift_variant	19/19	ENST00000373299.5	NP_001027392.1
STXBP1	NM_003165.6	c.*40delC		3_prime_UTR_variant	20/20	ENST00000373302.8	NP_003156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373299.5	c.1726delC	p.Gln576fs	frameshift_variant	19/19	1	NM_001032221.6	ENSP00000362396.2
STXBP1	ENST00000373302.8	c.*40delC		3_prime_UTR_variant	20/20	1	NM_003165.6	ENSP00000362399.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2013

c.1726delC:p.Gln576ArgfsX7 (Q576RfsX7) in exon 19 of the STXBP1 gene (NM_001032221.3). The normal sequence with the base that is deleted in braces is: CCCA{C}AGAA. The c.1726delC mutation in the STXBP1 gene causes a frameshift starting with codon Glutamine576, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 7 of the new reading frame. The protein that is produced by this deletion is predicted to have the last 19 amino acids replaced by 6 incorrect residues. The variant is found in STXBP1 panel(s). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs796053393; hg19: chr9-130453076;