rs6791

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006949.4(STXBP2):c.1576A>G(p.Ile526Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,250 control chromosomes in the GnomAD database, including 324,031 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 35051 hom., cov: 33)

Exomes 𝑓: 0.63 ( 288980 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.234

Variant links:

Genes affected

STXBP2 (HGNC:11445): (syntaxin binding protein 2) This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

STXBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.451353E-7).

BP6

Variant 19-7647391-A-G is Benign according to our data. Variant chr19-7647391-A-G is described in ClinVar as [Benign]. Clinvar id is 260094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647391-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4 linkuse as main transcript	c.1576A>G	p.Ile526Val	missense_variant	18/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10 linkuse as main transcript	c.1576A>G	p.Ile526Val	missense_variant	18/19	1	NM_006949.4	ENSP00000221283	P4	Q15833-1

Frequencies

GnomAD3 genomes

AF:

0.673

AC:

102229

AN:

151992

Hom.:

35002

Cov.:

show subpopulations

Gnomad AFR

AF:

0.772

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.675

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.824

Gnomad SAS

AF:

0.506

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.648

GnomAD3 exomes

AF:

0.634

AC:

156856

AN:

247224

Hom.:

50816

AF XY:

0.623

AC XY:

83842

AN XY:

134664

show subpopulations

Gnomad AFR exome

AF:

0.776

Gnomad AMR exome

AF:

0.647

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.815

Gnomad SAS exome

AF:

0.494

Gnomad FIN exome

AF:

0.728

Gnomad NFE exome

AF:

0.613

Gnomad OTH exome

AF:

0.635

GnomAD4 exome

AF:

0.625

AC:

913822

AN:

1461140

Hom.:

288980

Cov.:

AF XY:

0.621

AC XY:

451111

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.783

Gnomad4 AMR exome

AF:

0.655

Gnomad4 ASJ exome

AF:

0.509

Gnomad4 EAS exome

AF:

0.849

Gnomad4 SAS exome

AF:

0.492

Gnomad4 FIN exome

AF:

0.721

Gnomad4 NFE exome

AF:

0.620

Gnomad4 OTH exome

AF:

0.634

GnomAD4 genome

AF:

0.673

AC:

102340

AN:

152110

Hom.:

35051

Cov.:

AF XY:

0.676

AC XY:

50271

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.772

Gnomad4 AMR

AF:

0.674

Gnomad4 ASJ

AF:

0.505

Gnomad4 EAS

AF:

0.823

Gnomad4 SAS

AF:

0.507

Gnomad4 FIN

AF:

0.735

Gnomad4 NFE

AF:

0.612

Gnomad4 OTH

AF:

0.651

Alfa

AF:

0.621

Hom.:

37556

Bravo

AF:

0.678

TwinsUK

AF:

0.632

AC:

2345

ALSPAC

AF:

0.616

AC:

2375

ESP6500AA

AF:

0.775

AC:

3404

ESP6500EA

AF:

0.612

AC:

5251

ExAC

AF:

0.632

AC:

76700

Asia WGS

AF:

0.676

AC:

2352

AN:

3478

EpiCase

AF:

0.609

EpiControl

AF:

0.602

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Familial hemophagocytic lymphohistiocytosis 5

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hemophagocytic lymphohistiocytosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.028

DANN

Benign

0.25

DEOGEN2

Benign

0.058

.;T;.;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.060

T;T;T;T

MetaRNN

Benign

9.5e-7

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.75

.;N;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

0.59

N;N;N;.

REVEL

Benign

0.11

Sift

Benign

0.54

T;T;T;.

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.010

MPC

0.20

ClinPred

0.0018

GERP RS

-0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.025

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over