Genetic Variant NM_006949.4:c.8C>A (chr19-7637157-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_006949.4(STXBP2):c.8C>A(p.Pro3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,752 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 9.2e-7 ( 0 hom. )

Consequence

STXBP2
NM_006949.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

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 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STXBP2	NM_006949.4	MANE Select	c.8C>A	p.Pro3His	missense	Exon 1 of 19	NP_008880.2	Q15833-1
STXBP2	NM_001272034.2		c.8C>A	p.Pro3His	missense	Exon 1 of 19	NP_001258963.1	Q15833-3
STXBP2	NM_001127396.3		c.8C>A	p.Pro3His	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.8C>A	p.Pro3His	missense	Exon 1 of 19	ENSP00000221283.4	Q15833-1
STXBP2	ENST00000414284.6	TSL:1	c.8C>A	p.Pro3His	missense	Exon 1 of 19	ENSP00000409471.1	Q15833-2
STXBP2	ENST00000597068.5	TSL:1	n.8C>A		non_coding_transcript_exon	Exon 1 of 19	ENSP00000471327.1	M0R0M7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089752

Hom.:

Cov.:

AF XY:

0.00000194

AC XY:

AN XY:

514800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22988

American (AMR)

AF:

0.00

AC:

AN:

8412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14368

East Asian (EAS)

AF:

0.00

AC:

AN:

26526

South Asian (SAS)

AF:

0.0000504

AC:

AN:

19854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3896

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920208

Other (OTH)

AF:

0.00

AC:

AN:

43808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

0.065

MutationAssessor

Uncertain

2.4

PhyloP100

1.2

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.36

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.32

MutPred

0.36

Gain of MoRF binding (P = 0.0474)

MVP

0.93

MPC

0.95

ClinPred

0.98

GERP RS

4.5

PromoterAI

0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.33

gMVP

0.34

Mutation Taster

=47/53

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