rs121918318

Variant names:

• chr9-127663314-G-A
• rs121918318
• NM_003165.6:c.539G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_001032221.6(STXBP1):​c.539G>A​(p.Cys180Tyr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.91

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 Likely_pathogenic. Variant got 9 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 9-127663314-G-A is Pathogenic according to our data. Variant chr9-127663314-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6727.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-127663314-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.539G>A	p.Cys180Tyr	missense_variant	Exon 7 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.539G>A	p.Cys180Tyr	missense_variant	Exon 7 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.539G>A	p.Cys180Tyr	missense_variant	Exon 7 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.539G>A	p.Cys180Tyr	missense_variant	Exon 7 of 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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 30, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C180Y pathogenic mutation (also known as c.539G>A), located in coding exon 7 of the STXBP1 gene, results from a G to A substitution at nucleotide position 539. The cysteine at codon 180 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported as a de novo occurrence in an individual with epileptic encephalopathy (Saitsu H et al. Nat. Genet., 2008 Jun;40:782-8). Functional studies indicate that this mutation impairs membrane vesicle fusion (Martin S et al. Cell Rep, 2014 Oct;9:206-18). Based on internal structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Colbert KN et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Jul;110:12637-42). In addition, a different alteration located at the same position, p.C180R (c.538T>C) was detected as a de novo occurrence in a male individual with Rett-like syndrome (Lopes, et al. J. Med. Genet. 2016 Mar;53(3):190-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Developmental and epileptic encephalopathy, 4 Pathogenic:1

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;.;T;.;T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	.;.;M;.;.;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-10	.;.;D;.;.;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;.;D;.;.;.;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;.;D
Polyphen		1.0	.;.;D;.;.;.;D
Vest4		0.95, 0.95
MutPred		0.85		.;.;Loss of catalytic residue at T182 (P = 0.1224);Loss of catalytic residue at T182 (P = 0.1224);Loss of catalytic residue at T182 (P = 0.1224);.;Loss of catalytic residue at T182 (P = 0.1224);
MVP		0.93
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98

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: rs121918318; hg19: chr9-130425593;