rs61736586

chr19-7647478-A-G

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.1663A>G(p.Arg555Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,606,776 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.07

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=0.0067243576).
• BP6: Variant 19-7647478-A-G is Benign according to our data. Variant chr19-7647478-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7647478-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00844 (1285/152214) while in subpopulation AFR AF= 0.028 (1162/41514). AF 95% confidence interval is 0.0267. There are 16 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP2	NM_006949.4	c.1663A>G	p.Arg555Gly	missense_variant	18/19	ENST00000221283.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP2	ENST00000221283.10	c.1663A>G	p.Arg555Gly	missense_variant	18/19	1	NM_006949.4	P4

Frequencies

GnomAD3 genomes AF: 0.00844 AC: 1283 AN: 152096 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00869

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00289 AC: 676 AN: 233976 Hom.: 6 AF XY: 0.00225 AC XY: 287 AN XY: 127380

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00845

Gnomad SAS exome AF: 0.000542

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00107 AC: 1554 AN: 1454562 Hom.: 18 Cov.: 77 AF XY: 0.000947 AC XY: 685 AN XY: 723254

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00167

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00530

Gnomad4 SAS exome AF: 0.000550

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000577

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00844 AC: 1285 AN: 152214 Hom.: 16 Cov.: 33 AF XY: 0.00842 AC XY: 627 AN XY: 74424

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00871

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00192 Hom.: 2

Bravo AF: 0.00909

ESP6500AA AF: 0.0257 AC: 113

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

STXBP2: BP4, BS1, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D;D;D;.
REVEL	Benign	0.27
Sift	Benign	0.035	D;D;D;.
Sift4G	Uncertain	0.038	D;D;D;T
Polyphen		0.0010, 0.0	.;B;B;.
Vest4		0.42
MVP		0.63
MPC		0.31
ClinPred		0.016	T
GERP RS		-3.8
Varity_R		0.28
gMVP		0.58

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: rs61736586; hg19: chr19-7712364;