rs140148806

Variant names:

• chr19-7645196-G-C
• rs140148806
• NM_006949.4:c.1247-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-7645196-G-C
• chr19-7645196-G-A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_006949.4(STXBP2):​c.1247-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,559,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000415685: in vitro functional analysis demonstrated that the variant disrupts binding to syntaxin 11, which is also associated with familial hemophagocytic lymphohistiocytosis (zur Stadt et al. 2009" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: STXBP2 NM_006949.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 9.22
• Publications: 23 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: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, PanelApp Australia, 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000415685: in vitro functional analysis demonstrated that the variant disrupts binding to syntaxin 11, which is also associated with familial hemophagocytic lymphohistiocytosis (zur Stadt et al. 2009; Pagel et al. 2012).; SCV002570833: Experimental evidence has shown that the variant results in the partial deletion of exon 15 and the insertion of 56bp from the intronic sequence, leading to a frameshift after codon 416 and a protein of almost the same size as wild-type STXBP2 (p.Val417LeufsX126)(e.g. zur Stadt_2009, Cote_2009).; SCV000829469: Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 15 (PMID: 19884660).
• PP5: Variant 19-7645196-G-C is Pathogenic according to our data. Variant chr19-7645196-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 330555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006949.4. 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.1247-1G>C		splice_acceptor intron	N/A	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.1280-1G>C		splice_acceptor intron	N/A	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.1238-1G>C		splice_acceptor intron	N/A	NP_001120868.1	Q15833-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.1247-1G>C		splice_acceptor intron	N/A	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.1238-1G>C		splice_acceptor intron	N/A	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.1222-1G>C		splice_acceptor intron	N/A	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000202 AC: 34 AN: 168500 AF XY: 0.000235

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000401

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000301 AC: 423 AN: 1406964 Hom.: 0 Cov.: 34 AF XY: 0.000314 AC XY: 218 AN XY: 694716

African (AFR) AF: 0.000125 AC: 4 AN: 32010

American (AMR) AF: 0.0000541 AC: 2 AN: 36952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25294

East Asian (EAS) AF: 0.00 AC: 0 AN: 36486

South Asian (SAS) AF: 0.000188 AC: 15 AN: 79978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.000361 AC: 391 AN: 1082616

Other (OTH) AF: 0.000189 AC: 11 AN: 58304

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152216 Hom.: 0 Cov.: 34 AF XY: 0.000215 AC XY: 16 AN XY: 74372

African (AFR) AF: 0.0000482 AC: 2 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000154 AC: 18

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Familial hemophagocytic lymphohistiocytosis 5 (10)
7	-	-	not provided (7)
2	-	-	Familial hemophagocytic lymphohistiocytosis (2)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITHOUT MICROVILLUS INCLUSION DISEASE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		9.2
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 8
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140148806; hg19: chr19-7710082;