chr19-7645248-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006949.4(STXBP2):c.1298C>T(p.Ala433Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,582,430 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A433A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 4 hom., cov: 34)

Exomes 𝑓: 0.011 ( 125 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.06

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003764242).

BP6

Variant 19-7645248-C-T is Benign according to our data. Variant chr19-7645248-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00866 (1319/152360) while in subpopulation AMR AF = 0.0152 (232/15306). AF 95% confidence interval is 0.0136. There are 4 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.1298C>T	p.Ala433Val	missense_variant	Exon 15 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.1298C>T	p.Ala433Val	missense_variant	Exon 15 of 19	1	NM_006949.4	ENSP00000221283.4	Q15833-1
ENSG00000268400	ENST00000698368.1 link	n.*1401C>T		non_coding_transcript_exon_variant	Exon 17 of 20			ENSP00000513686.1	A0A8V8TM65
ENSG00000268400	ENST00000698368.1 link	n.*1401C>T		3_prime_UTR_variant	Exon 17 of 20			ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.00866

AC:

1318

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00329

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00826

AC:

1662

AN:

201122

AF XY:

0.00839

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00956

Gnomad ASJ exome

AF:

0.00372

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00207

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0113

AC:

16143

AN:

1430070

Hom.:

125

Cov.:

AF XY:

0.0113

AC XY:

8008

AN XY:

708292

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

32804

American (AMR)

AF:

0.00988

AC:

402

AN:

40708

Ashkenazi Jewish (ASJ)

AF:

0.00407

AC:

104

AN:

25522

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38180

South Asian (SAS)

AF:

0.00620

AC:

509

AN:

82054

European-Finnish (FIN)

AF:

0.00325

AC:

165

AN:

50750

Middle Eastern (MID)

AF:

0.0232

AC:

133

AN:

5724

European-Non Finnish (NFE)

AF:

0.0129

AC:

14168

AN:

1095198

Other (OTH)

AF:

0.0103

AC:

607

AN:

59130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

916

1833

2749

3666

4582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00866

AC:

1319

AN:

152360

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

608

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41586

American (AMR)

AF:

0.0152

AC:

232

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00373

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00329

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0128

AC:

873

AN:

68022

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00876

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00621

AC:

747

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 1.6% of total chromosomes in ExAC, 2.7% (44/1612) of Latino chromosomes -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 5

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

STXBP2: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autoinflammatory syndrome

Benign:1

Apr 04, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.097

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.15

.;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.86

.;L;.

PhyloP100

1.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.037, 0.030

.;B;B

Vest4

0.22

MVP

0.64

MPC

0.24

ClinPred

0.0019

GERP RS

3.0

Varity_R

0.13

gMVP

0.37

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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chr19-7645248-C-T

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