19-7647401-G-C

Position:

• chr19-7647401-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting 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).

• 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:8 B:2 O:1
• Conservation: PhyloP100: 5.75

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]

ENSG00000268400 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08124885).
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP2	NM_006949.4	c.1586G>C	p.Arg529Pro	missense_variant	18/19	ENST00000221283.10	NP_008880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP2	ENST00000221283.10	c.1586G>C	p.Arg529Pro	missense_variant	18/19	1	NM_006949.4	ENSP00000221283.4
ENSG00000268400	ENST00000698368.1	n.*1689G>C		non_coding_transcript_exon_variant	20/20			ENSP00000513686.1
ENSG00000268400	ENST00000698368.1	n.*1689G>C		3_prime_UTR_variant	20/20			ENSP00000513686.1

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

GnomAD3 exomes AF: 0.00140 AC: 347 AN: 247752 Hom.: 0 AF XY: 0.00136 AC XY: 184 AN XY: 134828

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 SAS exome AF: 0.0000982

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

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.00197

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

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00189

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:8 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2023	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 0.0014 in 247752 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.0014 vs 0.0022), allowing no conclusion about variant significance. c.1586G>C has been reported in the literature in heterozygous individuals with clinically-suspected Familial Hemophagocytic Lymphohistiocytosis who were also heterozygous for a variant in PRF1 (e.g. Zhang_2014, Noori_2023). The variant was also found in a homozygous individual with haemophilia A without strong evidence for causality (Carrel_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. One publication reports experimental evidence evaluating an impact on protein function, suggesting normal cytotoxic activity of CD8+ T and NK cells in vitro, however, it does not allow convincing conclusions about the variant effect in disease (Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 34050687, 36706356, 24916509). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2024	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) -
association, criteria provided, single submitter	case-control	Population Bio, Inc.	Aug 30, 2022	STXBP2 variant c.1586G>C (rs35490401) is associated with Progressive multifocal leukoencephalopathy (PML, ORPHA:217260). -

Familial hemophagocytic lymphohistiocytosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 09, 2017

- -

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

STXBP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.081	T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	.;M;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.0	D;D;D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0, 0.99	.;D;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

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

Publications

LitVar

Other links and lift over

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