chr9-127660116-C-T

Position:

• chr9-127660116-C-T

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.325+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,104 control chromosomes in the GnomAD database, including 37 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 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (34 hom.)
• Consequence: STXBP1 NM_003165.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001561
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.04

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 9-127660116-C-T is Benign according to our data. Variant chr9-127660116-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127660116-C-T is described in Lovd as [Likely_benign]. Variant chr9-127660116-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00336 (512/152278) while in subpopulation SAS AF= 0.0124 (60/4820). AF 95% confidence interval is 0.00993. There are 3 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 512 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_001032221.6	c.325+8C>T		splice_region_variant, intron_variant		ENST00000373299.5
STXBP1	NM_003165.6	c.325+8C>T		splice_region_variant, intron_variant		ENST00000373302.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373299.5	c.325+8C>T		splice_region_variant, intron_variant		1	NM_001032221.6	A1
STXBP1	ENST00000373302.8	c.325+8C>T		splice_region_variant, intron_variant		1	NM_003165.6	P3

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 512 AN: 152160 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00511

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00381 AC: 957 AN: 251450 Hom.: 8 AF XY: 0.00434 AC XY: 590 AN XY: 135896

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00504 AC: 7364 AN: 1461826 Hom.: 34 Cov.: 31 AF XY: 0.00531 AC XY: 3863 AN XY: 727230

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00515

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152278 Hom.: 3 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74456

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00511

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00343 Hom.: 0

Bravo AF: 0.00293

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2012	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	STXBP1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -

Developmental and epileptic encephalopathy, 4 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 09, 2022	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.17
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
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: rs117372398; hg19: chr9-130422395;