9-127612405-T-G

Variant names:

• chr9-127612405-T-G
• NM_003165.6:c.2T>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Supporting PM2 PP5_Very_Strong

The NM_001032221.6(STXBP1):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_001032221.6 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0360

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.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 42 CDS bases. Genomic position: 127651607. Lost 0.024 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127612405-T-G is Pathogenic according to our data. Variant chr9-127612405-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2019337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.2T>G	p.Met1?	start_lost	Exon 1 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.2T>G	p.Met1?	start_lost	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.2T>G	p.Met1?	start_lost	Exon 1 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.2T>G	p.Met1?	start_lost	Exon 1 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Jul 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individual(s) with epileptic encephalopathy (PMID: 34489640). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the STXBP1 mRNA. The next in-frame methionine is located at codon 15. -

Developmental and epileptic encephalopathy, 4 Pathogenic:1

Nov 18, 2024

Servicio de Genética Del Instituto Nacional de Salud Del Niño, Ministerio de Salud

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant NM_001032221.6:c.2T>G (p.Met1?) changes the first nucleotide of the coding region, potentially disrupting the initiation of translation. This variant is predicted to affect protein synthesis, with the possibility of preventing normal translation initiation. Based on ACMG/AMP guidelines, this variant meets the criteria for PS2, PM2, PVS1, and PP5, supporting its classification as pathogenic. The evidence is based on the potential loss of the initiation codon and the predicted functional consequence of this disruption -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	.;T;.;T;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.90	D;D;D;D;.
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
PROVEAN	Benign	-1.1	N;.;.;N;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;D;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.48
MutPred		0.99		Gain of methylation at M1 (P = 0.0174);Gain of methylation at M1 (P = 0.0174);Gain of methylation at M1 (P = 0.0174);Gain of methylation at M1 (P = 0.0174);Gain of methylation at M1 (P = 0.0174);
MVP		0.84
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.77
gMVP		0.83

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: chr9-130374684;