chr19-7646335-T-A

Variant names:

• chr19-7646335-T-A
• rs10001
• NM_006949.4:c.1443T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006949.4(STXBP2):​c.1443T>A​(p.Asp481Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D481N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP2 NM_006949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.00
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1443T>A	p.Asp481Glu	missense	Exon 16 of 19	NP_008880.2	Q15833-1
	STXBP2	NM_001272034.2		c.1476T>A	p.Asp492Glu	missense	Exon 16 of 19	NP_001258963.1	Q15833-3
	STXBP2	NM_001127396.3		c.1434T>A	p.Asp478Glu	missense	Exon 16 of 19	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.1443T>A	p.Asp481Glu	missense	Exon 16 of 19	ENSP00000221283.4	Q15833-1
	STXBP2	ENST00000414284.6	TSL:1	c.1434T>A	p.Asp478Glu	missense	Exon 16 of 19	ENSP00000409471.1	Q15833-2
	STXBP2	ENST00000597068.5	TSL:1	n.*191T>A		non_coding_transcript_exon	Exon 16 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453720 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 722364

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.00 AC: 0 AN: 84744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108790

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hemophagocytic lymphohistiocytosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	6.3
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.34	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.58		Gain of ubiquitination at K480 (P = 0.1204)
MVP		0.64
MPC		0.24
ClinPred		0.99	D
GERP RS		-3.7
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.76
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs10001; hg19: chr19-7711221;