Genetic Variant STXBP2:p.Ala8Thr (chr19-7637171-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006949.4(STXBP2):c.22G>A(p.Ala8Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.17

Publications

0 publications found

Variant links:

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 links:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

PCP2 (HGNC:30209): (Purkinje cell protein 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within rhodopsin mediated signaling pathway. Predicted to be located in neuronal cell body. [provided by Alliance of Genome Resources, Apr 2022]

PCP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4082095).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STXBP2	NM_006949.4	MANE Select	c.22G>A	p.Ala8Thr	missense	Exon 1 of 19	NP_008880.2	Q15833-1
STXBP2	NM_001272034.2		c.22G>A	p.Ala8Thr	missense	Exon 1 of 19	NP_001258963.1	Q15833-3
STXBP2	NM_001127396.3		c.22G>A	p.Ala8Thr	missense	Exon 1 of 19	NP_001120868.1	Q15833-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STXBP2	ENST00000221283.10	TSL:1 MANE Select	c.22G>A	p.Ala8Thr	missense	Exon 1 of 19	ENSP00000221283.4	Q15833-1
STXBP2	ENST00000414284.6	TSL:1	c.22G>A	p.Ala8Thr	missense	Exon 1 of 19	ENSP00000409471.1	Q15833-2
STXBP2	ENST00000597068.5	TSL:1	n.22G>A		non_coding_transcript_exon	Exon 1 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1090842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

515358

African (AFR)

AF:

0.00

AC:

AN:

22996

American (AMR)

AF:

0.00

AC:

AN:

8412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14370

East Asian (EAS)

AF:

0.00

AC:

AN:

26530

South Asian (SAS)

AF:

0.00

AC:

AN:

19980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4040

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920376

Other (OTH)

AF:

0.00

AC:

AN:

43846

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hemophagocytic lymphohistiocytosis 5 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

Eigen

Benign

0.092

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

PhyloP100

5.2

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.82

REVEL

Benign

0.20

Sift

Benign

0.10

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.26

MutPred

0.40

Gain of methylation at K13 (P = 0.0828)

MVP

0.82

MPC

0.36

ClinPred

0.88

GERP RS

4.5

PromoterAI

0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.18

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over