9-127668083-T-G

Position:

• chr9-127668083-T-G

Variant summary

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

The NM_001032221.6(STXBP1):​c.798T>G​(p.Tyr266*) variant causes a stop gained change involving the alteration of a non-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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.98

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127668083-T-G is Pathogenic according to our data. Variant chr9-127668083-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 239512.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_003165.6	c.798T>G	p.Tyr266*	stop_gained	10/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.798T>G	p.Tyr266*	stop_gained	10/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.798T>G	p.Tyr266*	stop_gained	10/20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.798T>G	p.Tyr266*	stop_gained	10/19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 07, 2020

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 conditions. ClinVar contains an entry for this variant (Variation ID: 239512). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr266*) 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
Vest4		0.94, 0.95
GERP RS		-9.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs751170778; hg19: chr9-130430362;