9-127612428-G-A

Position:

• chr9-127612428-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PM5 PP2 BP4_Moderate BP6_Moderate

The NM_003165.6(STXBP1):​c.25G>A​(p.Val9Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V9L?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00300

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127612428-G-CT is described in ClinVar as [Pathogenic]. Clinvar id is 1202628.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20109111).
• BP6: Variant 9-127612428-G-A is Benign according to our data. Variant chr9-127612428-G-A is described in ClinVar as [Benign]. Clinvar id is 461292.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_003165.6	c.25G>A	p.Val9Ile	missense_variant	1/20	ENST00000373302.8
STXBP1	NM_001032221.6	c.25G>A	p.Val9Ile	missense_variant	1/19	ENST00000373299.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373302.8	c.25G>A	p.Val9Ile	missense_variant	1/20	1	NM_003165.6	P3
STXBP1	ENST00000373299.5	c.25G>A	p.Val9Ile	missense_variant	1/19	1	NM_001032221.6	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000437 AC: 1 AN: 229032 Hom.: 0 AF XY: 0.00000795 AC XY: 1 AN XY: 125798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445708 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.0021	.;T;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D;D;.
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.030	N;.;.;N;.
MutationTaster	Benign	0.91	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.14	N;.;.;N;.
REVEL	Benign	0.20
Sift	Benign	0.50	T;.;.;T;.
Sift4G	Benign	0.65	T;.;.;T;.
Polyphen		0.0010	B;.;.;B;.
Vest4		0.17
MutPred		0.42		Loss of ubiquitination at K7 (P = 0.0811);Loss of ubiquitination at K7 (P = 0.0811);Loss of ubiquitination at K7 (P = 0.0811);Loss of ubiquitination at K7 (P = 0.0811);Loss of ubiquitination at K7 (P = 0.0811);
MVP		0.20
MPC		1.0
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.055
gMVP		0.48

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: rs1262952349; hg19: chr9-130374707;