GeneBe

NM_006949.4:c.34dupG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006949.4(STXBP2):​c.34dupG​(p.Glu12GlyfsTer42) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E12E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

STXBP2
NM_006949.4 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.170

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]
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]

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-7637178-T-TG is Pathogenic according to our data. Variant chr19-7637178-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 2840748.Status of the report is criteria_provided_single_submitter, 1 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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
STXBP2
NM_006949.4
MANE Select
c.34dupGp.Glu12GlyfsTer42
frameshift splice_region
Exon 1 of 19NP_008880.2Q15833-1
STXBP2
NM_001272034.2
c.34dupGp.Glu12GlyfsTer42
frameshift splice_region
Exon 1 of 19NP_001258963.1Q15833-3
STXBP2
NM_001127396.3
c.34dupGp.Glu12GlyfsTer42
frameshift splice_region
Exon 1 of 19NP_001120868.1Q15833-2

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
STXBP2
ENST00000221283.10
TSL:1 MANE Select
c.34dupGp.Glu12GlyfsTer42
frameshift splice_region
Exon 1 of 19ENSP00000221283.4Q15833-1
STXBP2
ENST00000414284.6
TSL:1
c.34dupGp.Glu12GlyfsTer42
frameshift splice_region
Exon 1 of 19ENSP00000409471.1Q15833-2
STXBP2
ENST00000597068.5
TSL:1
n.34dupG
splice_region non_coding_transcript_exon
Exon 1 of 19ENSP00000471327.1M0R0M7

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151304
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000487
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1089872
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
514890
African (AFR)
AF:
0.00
AC:
0
AN:
22980
American (AMR)
AF:
0.00
AC:
0
AN:
8408
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
14370
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26522
South Asian (SAS)
AF:
0.00
AC:
0
AN:
19886
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
29952
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3694
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
920274
Other (OTH)
AF:
0.00
AC:
0
AN:
43786
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151304
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
73870
show subpopulations
African (AFR)
AF:
0.0000487
AC:
2
AN:
41104
American (AMR)
AF:
0.00
AC:
0
AN:
15210
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5134
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4764
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10534
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67798
Other (OTH)
AF:
0.00
AC:
0
AN:
2076
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
1
-
-
Familial hemophagocytic lymphohistiocytosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.17
Mutation Taster
=4/196
disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1269457253; hg19: chr19-7702064; API