dbSNP rs34450592: STXBP2:p.Glu283Glu (chr19-7642483-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_006949.4(STXBP2):c.849G>A(p.Glu283Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,078 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0094 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 21 hom. )

Consequence

STXBP2
NM_006949.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.915

Publications

3 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: AD, AR 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 19-7642483-G-A is Benign according to our data. Variant chr19-7642483-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260110.

BP7

Synonymous conserved (PhyloP=0.915 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00939 (1431/152342) while in subpopulation AFR AF = 0.0313 (1302/41568). AF 95% confidence interval is 0.0299. There are 24 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006949.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STXBP2	NM_006949.4	MANE Select	c.849G>A	p.Glu283Glu	synonymous	Exon 10 of 19	NP_008880.2
STXBP2	NM_001272034.2		c.882G>A	p.Glu294Glu	synonymous	Exon 10 of 19	NP_001258963.1
STXBP2	NM_001127396.3		c.840G>A	p.Glu280Glu	synonymous	Exon 10 of 19	NP_001120868.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.849G>A	p.Glu283Glu	synonymous	Exon 10 of 19	ENSP00000221283.4
STXBP2	ENST00000414284.6	TSL:1	c.840G>A	p.Glu280Glu	synonymous	Exon 10 of 19	ENSP00000409471.1
STXBP2	ENST00000597068.5	TSL:1	n.849G>A		non_coding_transcript_exon	Exon 10 of 19	ENSP00000471327.1

Frequencies

GnomAD3 genomes

AF:

0.00939

AC:

1429

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00885

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00310

AC:

779

AN:

251334

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.0330

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00805

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00115

AC:

1688

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

745

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0331

AC:

1109

AN:

33480

American (AMR)

AF:

0.00179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00524

AC:

208

AN:

39700

South Asian (SAS)

AF:

0.000545

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1112010

Other (OTH)

AF:

0.00262

AC:

158

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

121

242

363

484

605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00939

AC:

1431

AN:

152342

Hom.:

Cov.:

AF XY:

0.00934

AC XY:

696

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0313

AC:

1302

AN:

41568

American (AMR)

AF:

0.00307

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00887

AC:

AN:

5184

South Asian (SAS)

AF:

0.00124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68034

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00442

Hom.:

Bravo

AF:

0.0100

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoinflammatory syndrome (1)

Familial hemophagocytic lymphohistiocytosis (1)

Familial hemophagocytic lymphohistiocytosis 5 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.2

(source)

DANN

Benign

0.34

PhyloP100

0.92

PromoterAI

0.0098

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.8

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over