9-127612424-A-AGCTGTTGTCGG

Variant names:

• chr9-127612424-A-AGCTGTTGTCGG
• rs1564333757
• NM_003165.6:c.22_32dupGCTGTTGTCGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001032221.6(STXBP1):​c.22_32dupGCTGTTGTCGG​(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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G11G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_001032221.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.64
• Publications: 0 publications found

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]

STXBP1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 306 pathogenic variants in the truncated region.
• 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 rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.22_32dupGCTGTTGTCGG	p.Glu12LeufsTer11	frameshift_variant	Exon 1 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.22_32dupGCTGTTGTCGG	p.Glu12LeufsTer11	frameshift_variant	Exon 1 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.22_32dupGCTGTTGTCGG	p.Glu12LeufsTer11	frameshift_variant	Exon 1 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.22_32dupGCTGTTGTCGG	p.Glu12LeufsTer11	frameshift_variant	Exon 1 of 19	1	NM_001032221.6	ENSP00000362396.2

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

Developmental and epileptic encephalopathy Pathogenic:1

Jan 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1564333757; hg19: chr9-130374703;