rs146165014

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_006949.4(STXBP2):c.49G>A(p.Gly17Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,614,150 control chromosomes in the GnomAD database, including 1 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 0.0025 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 8.94

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009026319).

BP6

Variant 19-7638737-G-A is Benign according to our data. Variant chr19-7638737-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00246 (374/152264) while in subpopulation AFR AF= 0.0084 (349/41550). AF 95% confidence interval is 0.00767. There are 1 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.49G>A	p.Gly17Arg	missense_variant	Exon 2 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.49G>A	p.Gly17Arg	missense_variant	Exon 2 of 19	1	NM_006949.4	ENSP00000221283.4	Q15833-1
ENSG00000268400	ENST00000698368.1 link	n.*152G>A		non_coding_transcript_exon_variant	Exon 4 of 20			ENSP00000513686.1	A0A8V8TM65
ENSG00000268400	ENST00000698368.1 link	n.*152G>A		3_prime_UTR_variant	Exon 4 of 20			ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.00245

AC:

373

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00840

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000700

AC:

176

AN:

251462

Hom.:

AF XY:

0.000478

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00984

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000237

AC:

346

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

142

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00902

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.00246

AC:

374

AN:

152264

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00840

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000440

Hom.:

Bravo

AF:

0.00290

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000898

AC:

109

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Nov 17, 2022

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.49G>A (p.Gly17Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251462 control chromosomes, predominantly at a frequency of 0.0098 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal predicted allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.49G>A in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the STXBP2 gene demonstrated a sequence change, c.49G>A, in exon 2 that results in an amino acid change, p.Gly17Arg. This sequence change does not appear to have been previously described in individuals with STXBP2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.94% in the African subpopulation and 0.09% in the overall population (dbSNP rs146165014). The p.Gly17Arg change affects a highly conserved amino acid residue located in a domain of the STXBP2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly17Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly17Arg change remains unknown at this time. -

Jul 20, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hemophagocytic lymphohistiocytosis 5

Uncertain:1Benign:1

Mar 02, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Feb 18, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autoinflammatory syndrome

Uncertain:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

.;.;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.0090

T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.9

.;M;M;M

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.77

.;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.063

.;T;T;T

Sift4G

Benign

0.073

T;T;T;T

Polyphen

0.88, 0.93

.;.;P;P

Vest4

0.63, 0.70

MutPred

0.37

Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);

MVP

0.91

MPC

0.95

ClinPred

0.028

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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