rs200802985

Variant names:

• chr9-127660064-C-A
• NM_003165.6:c.281C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127660064-C-A
• chr9-127660064-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001032221.6(STXBP1):​c.281C>A​(p.Pro94Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P94L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001032221.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the STXBP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 79 curated benign missense variants. Gene score misZ: 4.263 (above the threshold of 3.09). Trascript score misZ: 5.8379 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.281C>A	p.Pro94Gln	missense_variant	Exon 5 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.281C>A	p.Pro94Gln	missense_variant	Exon 5 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.281C>A	p.Pro94Gln	missense_variant	Exon 5 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.281C>A	p.Pro94Gln	missense_variant	Exon 5 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	.;T;T;.;T;.;T;T;T;D;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.7	.;.;.;L;.;.;.;.;.;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	.;.;.;N;.;.;.;.;.;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.25	.;.;.;T;.;.;.;.;.;T;.
Sift4G	Benign	0.58	.;T;T;T;.;.;.;T;T;T;T
Polyphen		0.99, 0.99	.;.;.;D;.;.;.;.;.;D;.
Vest4		0.59, 0.59
MutPred		0.41		.;.;.;Loss of ubiquitination at K92 (P = 0.0454);Loss of ubiquitination at K92 (P = 0.0454);Loss of ubiquitination at K92 (P = 0.0454);.;.;.;Loss of ubiquitination at K92 (P = 0.0454);.;
MVP		0.52
MPC		2.3
ClinPred		0.94	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.74

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.

Other links and lift over

hg19: chr9-130422343;