rs2303113

Variant names:

• chr19-7647531-A-G
• rs2303113
• NM_006949.4:c.1696+20A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001272034.2(STXBP2):​c.1729+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,580,132 control chromosomes in the GnomAD database, including 7,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1506 hom., cov: 32)
  • Exomes 𝑓: 0.037 (6143 hom.)
• Consequence: STXBP2 NM_001272034.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0560
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-7647531-A-G is Benign according to our data. Variant chr19-7647531-A-G is described in ClinVar as Benign. ClinVar VariationId is 260099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272034.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	NM_006949.4	MANE Select	c.1696+20A>G		intron	N/A	NP_008880.2
	STXBP2	NM_001272034.2		c.1729+20A>G		intron	N/A	NP_001258963.1
	STXBP2	NM_001127396.3		c.1687+20A>G		intron	N/A	NP_001120868.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.1696+20A>G		intron	N/A	ENSP00000221283.4
	STXBP2	ENST00000414284.6	TSL:1	c.1687+20A>G		intron	N/A	ENSP00000409471.1
	STXBP2	ENST00000597068.5	TSL:1	n.*444+20A>G		intron	N/A	ENSP00000471327.1

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14152 AN: 151726 Hom.: 1498 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0364

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.0922

Gnomad FIN AF: 0.0719

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0717

GnomAD2 exomes AF: 0.0834 AC: 16397 AN: 196508 AF XY: 0.0771

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.479

Gnomad FIN exome AF: 0.0653

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0369 AC: 52760 AN: 1428288 Hom.: 6143 Cov.: 74 AF XY: 0.0372 AC XY: 26363 AN XY: 707920

African (AFR) AF: 0.194 AC: 6254 AN: 32268

American (AMR) AF: 0.100 AC: 3955 AN: 39438

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 831 AN: 25480

East Asian (EAS) AF: 0.491 AC: 18268 AN: 37226

South Asian (SAS) AF: 0.0712 AC: 5952 AN: 83554

European-Finnish (FIN) AF: 0.0636 AC: 3262 AN: 51320

Middle Eastern (MID) AF: 0.0248 AC: 139 AN: 5614

European-Non Finnish (NFE) AF: 0.00958 AC: 10486 AN: 1094332

Other (OTH) AF: 0.0612 AC: 3613 AN: 59056

GnomAD4 genome AF: 0.0934 AC: 14185 AN: 151844 Hom.: 1506 Cov.: 32 AF XY: 0.0992 AC XY: 7362 AN XY: 74230

African (AFR) AF: 0.188 AC: 7796 AN: 41412

American (AMR) AF: 0.106 AC: 1619 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 126 AN: 3464

East Asian (EAS) AF: 0.482 AC: 2469 AN: 5124

South Asian (SAS) AF: 0.0923 AC: 441 AN: 4778

European-Finnish (FIN) AF: 0.0719 AC: 761 AN: 10578

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 813 AN: 67898

Other (OTH) AF: 0.0714 AC: 150 AN: 2100

Alfa AF: 0.0512 Hom.: 120

Bravo AF: 0.101

Asia WGS AF: 0.258 AC: 894 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Familial hemophagocytic lymphohistiocytosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-0.056
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2303113; hg19: chr19-7712417; COSMIC: COSV55406351; COSMIC: COSV55406351;