rs150174842

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006949.4(STXBP2):c.1459G>A(p.Val487Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,611,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V487L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.33

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

familial hemophagocytic lymphohistiocytosis 5
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
hereditary hemophagocytic lymphohistiocytosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microvillus inclusion disease
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

STXBP2 links:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01370734).

BP6

Variant 19-7647168-G-A is Benign according to our data. Variant chr19-7647168-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 719480.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00173 (263/152328) while in subpopulation AFR AF = 0.00606 (252/41588). AF 95% confidence interval is 0.00544. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.1459G>A	p.Val487Met	missense_variant	Exon 17 of 19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STXBP2	ENST00000221283.10 link	c.1459G>A	p.Val487Met	missense_variant	Exon 17 of 19	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1 link	n.*1562G>A		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000513686.1
ENSG00000268400	ENST00000698368.1 link	n.*1562G>A		3_prime_UTR_variant	Exon 19 of 20			ENSP00000513686.1

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

263

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000424

AC:

103

AN:

242894

AF XY:

0.000286

show subpopulations

Gnomad AFR exome

AF:

0.00513

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000371

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1459536

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

726092

show subpopulations

African (AFR)

AF:

0.00553

AC:

185

AN:

33458

American (AMR)

AF:

0.000291

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.000353

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51818

Middle Eastern (MID)

AF:

0.000189

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111892

Other (OTH)

AF:

0.000265

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00173

AC:

263

AN:

152328

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00606

AC:

252

AN:

41588

American (AMR)

AF:

0.000522

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000156

Hom.:

Bravo

AF:

0.00210

ESP6500AA

AF:

0.00798

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000495

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autoinflammatory syndrome

Uncertain:1

Jun 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

STXBP2-related disorder

Benign:1

Mar 11, 2022

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

Feb 03, 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

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.50

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

0.0029

MutationAssessor

Benign

1.0

.;L;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.0

N;N;N;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.015

D;D;D;.

Sift4G

Uncertain

0.031

D;D;D;D

Polyphen

1.0, 0.99

.;D;D;.

Vest4

0.49

MVP

0.79

MPC

0.30

ClinPred

0.028

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.55

Mutation Taster

=81/19

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

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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