rs6791

chr19-7647391-A-Gchr19-7647391-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006949.4(STXBP2):c.1576A>G(p.Ile526Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,250 control chromosomes in the GnomAD database, including 324,031 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I526L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.67 (35051 hom., cov: 33)
  • Exomes 𝑓: 0.63 (288980 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.234

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.451353E-7).
• BP6: Variant 19-7647391-A-G is Benign according to our data. Variant chr19-7647391-A-G is described in ClinVar as [Benign]. Clinvar id is 260094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647391-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP2	NM_006949.4	c.1576A>G	p.Ile526Val	missense_variant	18/19	ENST00000221283.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP2	ENST00000221283.10	c.1576A>G	p.Ile526Val	missense_variant	18/19	1	NM_006949.4	P4

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102229 AN: 151992 Hom.: 35002 Cov.: 33

Gnomad AFR AF: 0.772

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.648

GnomAD3 exomes AF: 0.634 AC: 156856 AN: 247224 Hom.: 50816 AF XY: 0.623 AC XY: 83842 AN XY: 134664

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.815

Gnomad SAS exome AF: 0.494

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.613

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.625 AC: 913822 AN: 1461140 Hom.: 288980 Cov.: 88 AF XY: 0.621 AC XY: 451111 AN XY: 726860

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.655

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.849

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.721

Gnomad4 NFE exome AF: 0.620

Gnomad4 OTH exome AF: 0.634

GnomAD4 genome AF: 0.673 AC: 102340 AN: 152110 Hom.: 35051 Cov.: 33 AF XY: 0.676 AC XY: 50271 AN XY: 74366

Gnomad4 AFR AF: 0.772

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.823

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.735

Gnomad4 NFE AF: 0.612

Gnomad4 OTH AF: 0.651

Alfa AF: 0.621 Hom.: 37556

Bravo AF: 0.678

TwinsUK AF: 0.632 AC: 2345

ALSPAC AF: 0.616 AC: 2375

ESP6500AA AF: 0.775 AC: 3404

ESP6500EA AF: 0.612 AC: 5251

ExAC AF: 0.632 AC: 76700

Asia WGS AF: 0.676 AC: 2352 AN: 3478

EpiCase AF: 0.609

EpiControl AF: 0.602

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Familial hemophagocytic lymphohistiocytosis 5 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -

Familial hemophagocytic lymphohistiocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.028
Dann	Benign	0.25
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.060	T;T;T;T
MetaRNN	Benign	9.5e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.59	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.54	T;T;T;.
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.010
MPC		0.20
ClinPred		0.0018	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.025
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6791; hg19: chr19-7712277; COSMIC: COSV55401668; COSMIC: COSV55401668;