19-7647401-G-C

Variant names:

• chr19-7647401-G-C
• rs35490401
• NM_006949.4:c.1586G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_006949.4(STXBP2):​c.1586G>C​(p.Arg529Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00234 in 1,613,524 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R529Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications U:7 B:3 O:1
• Conservation: PhyloP100: 5.75
• Publications: 7 publications found

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

ENSG00000268400 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08124885).
• BP6: Variant 19-7647401-G-C is Benign according to our data. Variant chr19-7647401-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|association. ClinVar VariationId is 330559.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00137 (208/152316) while in subpopulation NFE AF = 0.00247 (168/68018). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006949.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.1586G>C	p.Arg529Pro	missense	Exon 18 of 19	NP_008880.2
	STXBP2	NM_001272034.2		c.1619G>C	p.Arg540Pro	missense	Exon 18 of 19	NP_001258963.1
	STXBP2	NM_001127396.3		c.1577G>C	p.Arg526Pro	missense	Exon 18 of 19	NP_001120868.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.1586G>C	p.Arg529Pro	missense	Exon 18 of 19	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.1577G>C	p.Arg526Pro	missense	Exon 18 of 19	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.*334G>C		non_coding_transcript_exon	Exon 18 of 19	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00140 AC: 347 AN: 247752 AF XY: 0.00136

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00244 AC: 3560 AN: 1461208 Hom.: 5 Cov.: 76 AF XY: 0.00224 AC XY: 1627 AN XY: 726912

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.00101 AC: 45 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86248

European-Finnish (FIN) AF: 0.00157 AC: 83 AN: 52858

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.00296 AC: 3290 AN: 1111952

Other (OTH) AF: 0.00197 AC: 119 AN: 60374

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00114 AC XY: 85 AN XY: 74480

African (AFR) AF: 0.000361 AC: 15 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00138

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00157 AC: 191

EpiCase AF: 0.00262

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity; association

Submissions summary: Uncertain:7 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Aug 15, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 17, 2025

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.1586G>C (p.Arg529Pro) 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 0.0023 in 1606572 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset), including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3-fold of the estimated maximal expected allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0022). The variant, c.1586G>C, has been reported in the literature in heterozygous state in individuals with clinically suspected Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, Noori_2023), and in homozygous state in an individual affected with haemophilia A (Carrel_2021). In addition, a publication reported experimental evidence evaluating an impact on protein function, and demonstrated normal (WT) activity for the variant protien (Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 24916509, 34050687, 36706356). ClinVar contains an entry for this variant (Variation ID: 330559). Based on the evidence outlined above, the variant was classified as likely benign.

not provided Uncertain:2 Other:1

Nov 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as an apparently homozygous variant in an individual with hemophilia A, but no additional phenotypic information was provided on this individual beyond the bleeding phenotype (PMID: 34050687); Identified in the heterozygous state in patients in the published literature with suspected familial hemophagocytic lymphohistiocytosis or a suspected bleeding disorder, but no variant was identified on the other allele (PMID: 24916509, 32935436, 36706356); 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: 32256442, 36706356, 32935436, 24916509, 34050687, 36588876)

Sep 30, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 30, 2022

Population Bio, Inc.

Significance: association

Review Status: criteria provided, single submitter

Collection Method: case-control

STXBP2 variant c.1586G>C (rs35490401) is associated with Progressive multifocal leukoencephalopathy (PML, ORPHA:217260).

Familial hemophagocytic lymphohistiocytosis Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autoinflammatory syndrome Uncertain:1

Mar 09, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

STXBP2-related disorder Benign:1

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Familial hemophagocytic lymphohistiocytosis 5 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.081	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.93
MPC		1.1
ClinPred		0.052	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.85
gMVP		0.79
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35490401; hg19: chr19-7712287; COSMIC: COSV55401574; COSMIC: COSV55401574;