rs199827018

Positions:

• chr9-127660022-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003165.6(STXBP1):​c.247-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,778 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: STXBP1 NM_003165.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002704
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.467

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-127660022-A-G is Benign according to our data. Variant chr9-127660022-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 139344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127660022-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00314 (477/151962) while in subpopulation NFE AF= 0.0043 (292/67954). AF 95% confidence interval is 0.00389. There are 0 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 477 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_001032221.6	c.247-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373299.5
STXBP1	NM_003165.6	c.247-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373302.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373299.5	c.247-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001032221.6	A1
STXBP1	ENST00000373302.8	c.247-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003165.6	P3

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 478 AN: 151844 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00928

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00430

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00359 AC: 902 AN: 251460 Hom.: 0 AF XY: 0.00338 AC XY: 460 AN XY: 135908

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00394 AC: 5766 AN: 1461816 Hom.: 18 Cov.: 31 AF XY: 0.00382 AC XY: 2780 AN XY: 727206

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00865

Gnomad4 NFE exome AF: 0.00425

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00314 AC: 477 AN: 151962 Hom.: 0 Cov.: 31 AF XY: 0.00337 AC XY: 250 AN XY: 74268

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00928

Gnomad4 NFE AF: 0.00430

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00254

EpiCase AF: 0.00365

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	STXBP1: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 4 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.99
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0020
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: rs199827018; hg19: chr9-130422301;