rs773360200

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_006949.4(STXBP2):c.1214G>A(p.Arg405Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,582 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. R405W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.82

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 19-7644720-G-A is Pathogenic according to our data. Variant chr19-7644720-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 538148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4 linkuse as main transcript	c.1214G>A	p.Arg405Gln	missense_variant	14/19	ENST00000221283.10	NP_008880.2	Q15833-1Q53GF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
STXBP2	ENST00000221283.10 linkuse as main transcript	c.1214G>A	p.Arg405Gln	missense_variant	14/19	1	NM_006949.4	ENSP00000221283.4	Q15833-1
ENSG00000268400	ENST00000698368.1 linkuse as main transcript	n.*1317G>A		non_coding_transcript_exon_variant	16/20			ENSP00000513686.1	A0A8V8TM65
ENSG00000268400	ENST00000698368.1 linkuse as main transcript	n.*1317G>A		3_prime_UTR_variant	16/20			ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250548

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461582

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 405 of the STXBP2 protein (p.Arg405Gln). This variant is present in population databases (rs773360200, gnomAD 0.02%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 19804848, 20798128, 23382066, 24194549, 28353193). This variant is also known as c.1205G>A. ClinVar contains an entry for this variant (Variation ID: 538148). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STXBP2 protein function. Experimental studies have shown that this missense change affects STXBP2 function (PMID: 19804848). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg405 amino acid residue in STXBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19804848, 28353193). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 05, 2024	- -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 02, 2023

Variant summary: STXBP2 c.1214G>A (p.Arg405Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250548 control chromosomes (gnomAD). c.1214G>A has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (examples: Cetica_2010, Pagel_2012, and Zhang_2020). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D;.

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.7

.;H;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.94

MutPred

0.96

.;Gain of catalytic residue at R405 (P = 0.0574);.;

MVP

0.94

MPC

0.95

ClinPred

0.98

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.89

Position offset: 1

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