NM_006949.4:c.1586G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_006949.4(STXBP2):c.1586G>C(p.Arg529Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00234 in 1,613,524 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 5 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:7B:3O:1

Conservation

PhyloP100: 5.75

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:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08124885).

BP6

Variant 19-7647401-G-C is Benign according to our data. Variant chr19-7647401-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, association]. Clinvar id is 330559.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, association=1, Uncertain_significance=6}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00137 (208/152316) while in subpopulation NFE AF= 0.00247 (168/68018). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.1586G>C	p.Arg529Pro	missense_variant	Exon 18 of 19	ENST00000221283.10	NP_008880.2	Q15833-1Q53GF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STXBP2	ENST00000221283.10 link	c.1586G>C	p.Arg529Pro	missense_variant	Exon 18 of 19	1	NM_006949.4	ENSP00000221283.4	Q15833-1
ENSG00000268400	ENST00000698368.1 link	n.*1689G>C		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000513686.1	A0A8V8TM65
ENSG00000268400	ENST00000698368.1 link	n.*1689G>C		3_prime_UTR_variant	Exon 20 of 20			ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

208

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00140

AC:

347

AN:

247752

Hom.:

AF XY:

0.00136

AC XY:

184

AN XY:

134828

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.000957

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00239

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00244

AC:

3560

AN:

1461208

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

1627

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00157

Gnomad4 NFE exome

AF:

0.00296

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00137

AC:

208

AN:

152316

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00247

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00157

AC:

191

EpiCase

AF:

0.00262

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity; association

Submissions summary: Uncertain:7Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STXBP2 c.1586G>C (p.Arg529Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 1606572 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset), including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3-fold of the estimated maximal expected allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0022). The variant, c.1586G>C, has been reported in the literature in heterozygous state in individuals with clinically suspected Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, Noori_2023), and in homozygous state in an individual affected with haemophilia A (Carrel_2021). In addition, a publication reported experimental evidence evaluating an impact on protein function, and demonstrated normal (WT) activity for the variant protien (Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 24916509, 34050687, 36706356). ClinVar contains an entry for this variant (Variation ID: 330559). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:2Other:1

Sep 30, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2022

Population Bio, Inc.

Significance: association

Review Status: criteria provided, single submitter

Collection Method: case-control

STXBP2 variant c.1586G>C (rs35490401) is associated with Progressive multifocal leukoencephalopathy (PML, ORPHA:217260). -

Nov 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as an apparently homozygous variant in an individual with hemophilia A, but no additional phenotypic information was provided on this individual beyond the bleeding phenotype (PMID: 34050687); Identified in the heterozygous state in patients in the published literature with suspected familial hemophagocytic lymphohistiocytosis or a suspected bleeding disorder, but no variant was identified on the other allele (PMID: 24916509, 32935436, 36706356); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32256442, 36706356, 32935436, 24916509, 34050687, 36588876) -

Familial hemophagocytic lymphohistiocytosis

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome

Uncertain:1

Mar 09, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

STXBP2-related disorder

Benign:1

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial hemophagocytic lymphohistiocytosis 5

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;T;.;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.081

T;T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.0

D;D;D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0, 0.99

.;D;D;.

Vest4

0.58

MVP

0.93

MPC

1.1

ClinPred

0.052

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.85

gMVP

0.79

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

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