9-127660116-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Publications

4 publications found

Variant links:

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]

STXBP1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Dravet syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

STXBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 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 Benign/Likely_benign. ClinVar VariationId is 94118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6 link	c.325+8C>T		splice_region_variant, intron_variant	Intron 5 of 19	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6 link	c.325+8C>T		splice_region_variant, intron_variant	Intron 5 of 18	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8 link	c.325+8C>T		splice_region_variant, intron_variant	Intron 5 of 19	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5 link	c.325+8C>T		splice_region_variant, intron_variant	Intron 5 of 18	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

512

AN:

152160

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00381

AC:

957

AN:

251450

AF XY:

0.00434

show subpopulations

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 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.:

Cov.:

AF XY:

0.00531

AC XY:

3863

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33476

American (AMR)

AF:

0.00145

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0148

AC:

1277

AN:

86258

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00515

AC:

5729

AN:

1111960

Other (OTH)

AF:

0.00379

AC:

229

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

399

798

1198

1597

1996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00336

AC:

512

AN:

152278

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000891

AC:

AN:

41548

American (AMR)

AF:

0.00150

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00511

AC:

348

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00343

Hom.:

Bravo

AF:

0.00293

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

May 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 30, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Sep 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

STXBP1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 4

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.17

(source)

DANN

Benign

0.72

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over