rs117761837

chr19-7643172-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006949.4(STXBP2):c.1034C>T(p.Thr345Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,038 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T345A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (196 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.80

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=0.018442452).
• BP6: Variant 19-7643172-C-T is Benign according to our data. Variant chr19-7643172-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7643172-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1534/152280) while in subpopulation NFE AF= 0.0162 (1105/68020). AF 95% confidence interval is 0.0154. There are 13 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP2	NM_006949.4	c.1034C>T	p.Thr345Met	missense_variant	13/19	ENST00000221283.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP2	ENST00000221283.10	c.1034C>T	p.Thr345Met	missense_variant	13/19	1	NM_006949.4	P4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152162 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.0108 AC: 2708 AN: 251274 Hom.: 18 AF XY: 0.0108 AC XY: 1469 AN XY: 135824

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00428

Gnomad FIN exome AF: 0.00588

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0143 AC: 20900 AN: 1461758 Hom.: 196 Cov.: 36 AF XY: 0.0144 AC XY: 10435 AN XY: 727174

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00675

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00444

Gnomad4 FIN exome AF: 0.00592

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0101 AC: 1534 AN: 152280 Hom.: 13 Cov.: 32 AF XY: 0.00908 AC XY: 676 AN XY: 74460

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0147 Hom.: 18

Bravo AF: 0.0103

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0109 AC: 1318

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely 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: Reported in 1 patient with -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	STXBP2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial hemophagocytic lymphohistiocytosis 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.34
MPC		0.86
ClinPred		0.0072	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.55
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs117761837; hg19: chr19-7708058;