rs796053374

Positions:

• chr9-127682510-G-C
• chr9-127682510-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_003165.6(STXBP1):​c.1652G>C​(p.Arg551Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R551C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.86

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127682509-C-T is described in Lovd as [Pathogenic].
• 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, 0.963
• PP5: Variant 9-127682510-G-C is Pathogenic according to our data. Variant chr9-127682510-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 207441.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.1652G>C	p.Arg551Pro	missense_variant	18/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1652G>C	p.Arg551Pro	missense_variant	18/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1652G>C	p.Arg551Pro	missense_variant	18/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.1652G>C	p.Arg551Pro	missense_variant	18/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

May 25, 2017

p.Arg551Pro (CGC>CCC): c.1652 G>C in exon 18 of the STXBP1 gene (NM_003165.2)The novel R551P missense change in the STXBP1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different amino acid substitution at the same codon, R551C, was previously reported as a de novo change in a patient with an autism spectrum disorder, although no additional information was provided regarding the patient's phenotype (Neale et al., 2012). The R551C variant subsequently has been reported as a de novo pathogenic variant in a child with infantile epileptic encephalopathy, intellectual disability, and ataxia (Weckhuysen et al., 2013). The R551P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R551P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. R551P alters a highly conserved position in the protein, and other missense variants have been reported in this region of the protein in the Human Gene Mutation Database in association with epilepsy (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T;.;T;.;T;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.8	.;.;D;.;.;.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	.;.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;D;.
Vest4		0.98, 0.98
MutPred		0.81		.;.;Loss of methylation at R551 (P = 0.0985);Loss of methylation at R551 (P = 0.0985);Loss of methylation at R551 (P = 0.0985);.;Loss of methylation at R551 (P = 0.0985);.;
MVP		0.94
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		1.0

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: rs796053374; hg19: chr9-130444789;