rs930347206

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_006949.4(STXBP2):c.389T>C(p.Leu130Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,614,036 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L130L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 6.05

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:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 19-7640963-T-C is Pathogenic according to our data. Variant chr19-7640963-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579782.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP2	NM_006949.4 link	c.389T>C	p.Leu130Ser	missense_variant	Exon 6 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.389T>C	p.Leu130Ser	missense_variant	Exon 6 of 19	1	NM_006949.4	ENSP00000221283.4	Q15833-1
ENSG00000268400	ENST00000698368.1 link	n.*492T>C		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000513686.1	A0A8V8TM65
ENSG00000268400	ENST00000698368.1 link	n.*492T>C		3_prime_UTR_variant	Exon 8 of 20			ENSP00000513686.1	A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.0000447

AC:

AN:

44718

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53414

Gnomad4 NFE exome

AF:

8.99e-7

AC:

AN:

1111998

Gnomad4 Remaining exome

AF:

0.0000828

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000785

AC:

0.000785032

AN:

0.000785032

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000478

AC:

0.000478469

AN:

0.000478469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.0000282

Hom.:

Bravo

AF:

0.000215

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5

Pathogenic:2Uncertain:1

Mar 21, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the STXBP2 protein (p.Leu130Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 22791290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 579782). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt STXBP2 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported in the homozygous state and in the heterozygous state together with a second STXBP2 variant in individuals with symptoms of hemophagocytic lymphohistiocytosis (PMID: 32542393, 22791290). The c.389T>C (p.Leu130Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/31360) and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is negative and the father is heterozygous for this variant. Based on the available evidence, the c.389T>C (p.Leu130Ser) variant is classified as Likely Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 12, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.389T>C (p.L130S) alteration is located in exon 6 (coding exon 6) of the STXBP2 gene. This alteration results from a T to C substitution at nucleotide position 389, causing the leucine (L) at amino acid position 130 to be replaced by a serine (S). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (1/31360) total alleles studied; however, this variant was flagged as a low confidence call. This variant has been identified in conjunction with other STXBP2 variants in an individual with features consistent with STXBP2-related hemophagocytic lymphohistiocytosis; in this instance, the variants were identified in trans (Al Hawas, 2012). This variant has been identified in the homozygous state and in conjunction with other STXBP2 variants in additional individuals, but clinical details were limited (Gadoury-Levesque, 2020). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Familial hemophagocytic lymphohistiocytosis

Pathogenic:1

Apr 16, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: STXBP2 c.389T>C (p.Leu130Ser) 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. In a structural analysis of of the protein, the variant mapped to the predicted syntaxin and soluble N-ethylmaleimidesensitive factor accessory protein receptor binding sites of Munc18-2 (Hackman_2013). The variant was absent in 251460 control chromosomes. c.389T>C has been reported in the literature in individuals affected with Hemophagocytic Lymphohistiocytosis including one homozygous patient, a compound heterozygous patient with a pathogenic variant on the second allele, and a patient who also carried an exon deletion without phase of the variants specified (AlHawas_2012, Gadoury-Levesque_2020). In experimental studies from a biallelic patient carrying the variant along with a pathogenic variant in trans, Munc18b was undetectable in platelets from the patient, suggesting the variant causes the production of an unstable Munc18b protein. Additionally, platelets from this patient exhibited a severe defect in release from both dense and alpha-granules and ADP/ATP was almost completely absent (Al Hawas_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22791290, 32542393, 24194549). ClinVar contains an entry for this variant (Variation ID: 579782). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Apr 02, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a partial deletion of the STXBP2 gene in a patient with features of hemophagocytic lymphohistiocytosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 32542393); Not observed at significant frequency in large population cohorts (gnomAD); 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: 32542393, 22791290, 24194549) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

.;.;.;D;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.6

.;.;.;M;.;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.9

.;.;D;D;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

.;.;D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;D;.

Vest4

0.98, 0.99

MutPred

0.80

.;.;.;Gain of disorder (P = 0.0132);.;.;

MVP

0.97

MPC

1.0

ClinPred

0.99

GERP RS

4.4

Varity_R

0.72

gMVP

0.94

Mutation Taster

=0/100

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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