Variant chr9-127666235-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_003165.6(STXBP1):c.733C>A(p.His245Asn) 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

STXBP1
NM_003165.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STXBP1. . Gene score misZ 4.263 (greater than the threshold 3.09). Trascript score misZ 5.8329 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 9-127666235-C-A is Pathogenic according to our data. Variant chr9-127666235-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1298373.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6 linkuse as main transcript	c.733C>A	p.His245Asn	missense_variant	9/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6 linkuse as main transcript	c.733C>A	p.His245Asn	missense_variant	9/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8 linkuse as main transcript	c.733C>A	p.His245Asn	missense_variant	9/20	1	NM_003165.6	ENSP00000362399	P3	P61764-2
STXBP1	ENST00000373299.5 linkuse as main transcript	c.733C>A	p.His245Asn	missense_variant	9/19	1	NM_001032221.6	ENSP00000362396	A1	P61764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 4

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pediatric Department, Xiangya Hospital, Central South University

Jan 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T;.;T;.;T;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;D;D;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.2

.;.;M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.6

.;.;D;.;.;.;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

.;.;D;.;.;.;D

Sift4G

Pathogenic

0.0

.;.;D;.;.;.;D

Polyphen

1.0

.;.;D;.;.;.;D

Vest4

0.84, 0.84

MutPred

0.94

.;.;Loss of catalytic residue at L247 (P = 0.0786);Loss of catalytic residue at L247 (P = 0.0786);Loss of catalytic residue at L247 (P = 0.0786);.;Loss of catalytic residue at L247 (P = 0.0786);

MVP

0.93

MPC

2.0

ClinPred

1.0

GERP RS

5.7

Varity_R

0.95

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over