rs61736587

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_006949.4(STXBP2):c.1621G>A(p.Gly541Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G541C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 8.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 19-7647436-G-A is Pathogenic according to our data. Variant chr19-7647436-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647436-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP2	NM_006949.4 linkuse as main transcript	c.1621G>A	p.Gly541Ser	missense_variant	18/19	ENST00000221283.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP2	ENST00000221283.10 linkuse as main transcript	c.1621G>A	p.Gly541Ser	missense_variant	18/19	1	NM_006949.4	P4	Q15833-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000234

AC:

AN:

248156

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

134664

show subpopulations

Gnomad AFR exome

AF:

0.000254

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000465

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000355

AC:

518

AN:

1461150

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

251

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000443

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000151

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000393

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 541 of the STXBP2 protein (p.Gly541Ser). This variant is present in population databases (rs61736587, gnomAD 0.05%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis type 5 (PMID: 20558610, 20798128, 20823128). ClinVar contains an entry for this variant (Variation ID: 30219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STXBP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STXBP2 function (PMID: 20798128, 24194549). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 08, 2022	PS3, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20798128). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic with strong evidence (ClinVar ID: VCV000030219). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	Published functional studies demonstrate the variant disrupts association of the protein with syntaxin 11, and functional assays show defective degranulation and cellular cytotoxicity (Cetica et al., 2010); 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: 20823128, 26320718, 23687090, 24194549, 32542393, 31589614, 35020838, 33162974, 20798128) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 10, 2017	- -

STXBP2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2023

The STXBP2 c.1621G>A variant is predicted to result in the amino acid substitution p.Gly541Ser. This variant was reported in the homozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL) who lacked variants in the PRF1, UNC13D, and STX11 genes (Cetica et al. 2010. PubMed ID: 20798128). It has also been reported along with a second STXBP2 variant in other patients with FHL (Meeths et al. 2010. PubMed ID: 20558610; Rohr et al. 2010. PubMed ID: 20823128). Functional data in Cetica et al. suggest the p.Gly541Ser substitution affects binding of the STXBP2 protein to its effectors. This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-7712322-G-A). It has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/30219). Taken together, this variant is interpreted as pathogenic. -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 27, 2023

Variant summary: STXBP2 c.1621G>A (p.Gly541Ser) 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 0.00023 in 248156 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00023 vs 0.0022), allowing no conclusion about variant significance. c.1621G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Cetica_2010, Pagel_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Cetica_2012). The most pronounced variant effect results in a defective protein and by defective cytotoxicity by T lymphocytes. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D;.;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

.;M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

D;D;D;.

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0020

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.99

MVP

0.98

MPC

0.60

ClinPred

0.84

GERP RS

5.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.95

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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