19-7642116-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006949.4(STXBP2):​c.661G>T​(p.Glu221*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

STXBP2
NM_006949.4 stop_gained, splice_region

Scores

5
1
1
Splicing: ADA: 0.7161
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.46
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-7642116-G-T is Pathogenic according to our data. Variant chr19-7642116-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2752778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STXBP2NM_006949.4 linkc.661G>T p.Glu221* stop_gained, splice_region_variant Exon 8 of 19 ENST00000221283.10 NP_008880.2 Q15833-1Q53GF4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STXBP2ENST00000221283.10 linkc.661G>T p.Glu221* stop_gained, splice_region_variant Exon 8 of 19 1 NM_006949.4 ENSP00000221283.4 Q15833-1
ENSG00000268400ENST00000698368.1 linkn.*764G>T splice_region_variant, non_coding_transcript_exon_variant Exon 10 of 20 ENSP00000513686.1 A0A8V8TM65
ENSG00000268400ENST00000698368.1 linkn.*764G>T 3_prime_UTR_variant Exon 10 of 20 ENSP00000513686.1 A0A8V8TM65

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 5 Pathogenic:1
Aug 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu221*) in the STXBP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STXBP2 are known to be pathogenic (PMID: 19804848, 22451424). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STXBP2-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
50
DANN
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
Vest4
0.89, 0.89
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.72
dbscSNV1_RF
Pathogenic
0.80
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-7707002; API