9-127612411-C-G

Variant names:

• chr9-127612411-C-G
• rs575515332
• NM_003165.6:c.8C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001032221.6(STXBP1):​c.8C>G​(p.Pro3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.438

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39134148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.8C>G	p.Pro3Arg	missense_variant	Exon 1 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.8C>G	p.Pro3Arg	missense_variant	Exon 1 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.8C>G	p.Pro3Arg	missense_variant	Exon 1 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.8C>G	p.Pro3Arg	missense_variant	Exon 1 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	.;T;.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;.
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Uncertain	0.067	D
MutationAssessor	Uncertain	2.0	M;.;.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;.;.;N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D;.;.;D;.
Sift4G	Uncertain	0.0070	D;.;.;D;.
Polyphen		0.98	D;.;.;D;.
Vest4		0.17
MutPred		0.51		Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);
MVP		0.40
MPC		1.6
ClinPred		0.68	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.78

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: rs575515332; hg19: chr9-130374690;