9-127612411-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001032221.6(STXBP1):c.8C>A(p.Pro3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,597,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

STXBP1
NM_001032221.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.438

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001032221.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32487357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6 link	c.8C>A	p.Pro3His	missense_variant	Exon 1 of 20	ENST00000373302.8	NP_003156.1	P61764-2
STXBP1	NM_001032221.6 link	c.8C>A	p.Pro3His	missense_variant	Exon 1 of 19	ENST00000373299.5	NP_001027392.1	P61764-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8 link	c.8C>A	p.Pro3His	missense_variant	Exon 1 of 20	1	NM_003165.6	ENSP00000362399.3		P61764-2
STXBP1	ENST00000373299.5 link	c.8C>A	p.Pro3His	missense_variant	Exon 1 of 19	1	NM_001032221.6	ENSP00000362396.2		P61764-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000132

AC:

AN:

228072

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000592

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000979

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31616

American (AMR)

AF:

0.00

AC:

AN:

43562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25588

East Asian (EAS)

AF:

0.00

AC:

AN:

38406

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104804

Other (OTH)

AF:

0.00

AC:

AN:

59490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41516

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67914

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

.;T;.;T;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;D;D;.

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Uncertain

0.015

MutationAssessor

Uncertain

2.0

M;.;.;M;.

PhyloP100

0.44

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.4

N;.;.;N;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

D;.;.;D;.

Sift4G

Uncertain

0.0070

D;.;.;D;.

Polyphen

1.0

D;.;.;D;.

Vest4

0.34

MutPred

0.41

Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);

MVP

0.42

MPC

2.2

ClinPred

0.70

GERP RS

2.7

PromoterAI

0.084

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.68

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-127612411-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over