19-7638737-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_006949.4(STXBP2):c.49G>A(p.Gly17Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0025 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
STXBP2
NM_006949.4 missense
NM_006949.4 missense
Scores
3
6
5
Clinical Significance
Conservation
PhyloP100: 8.94
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.009026319).
BP6
Variant 19-7638737-G-A is Benign according to our data. Variant chr19-7638737-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00246 (374/152264) while in subpopulation AFR AF= 0.0084 (349/41550). AF 95% confidence interval is 0.00767. There are 1 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP2 | NM_006949.4 | c.49G>A | p.Gly17Arg | missense_variant | 2/19 | ENST00000221283.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP2 | ENST00000221283.10 | c.49G>A | p.Gly17Arg | missense_variant | 2/19 | 1 | NM_006949.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00245 AC: 373AN: 152146Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000700 AC: 176AN: 251462Hom.: 0 AF XY: 0.000478 AC XY: 65AN XY: 135916
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GnomAD4 exome AF: 0.000237 AC: 346AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.000195 AC XY: 142AN XY: 727246
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GnomAD4 genome AF: 0.00246 AC: 374AN: 152264Hom.: 1 Cov.: 33 AF XY: 0.00240 AC XY: 179AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 20, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 28, 2022 | DNA sequence analysis of the STXBP2 gene demonstrated a sequence change, c.49G>A, in exon 2 that results in an amino acid change, p.Gly17Arg. This sequence change does not appear to have been previously described in individuals with STXBP2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.94% in the African subpopulation and 0.09% in the overall population (dbSNP rs146165014). The p.Gly17Arg change affects a highly conserved amino acid residue located in a domain of the STXBP2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly17Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly17Arg change remains unknown at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 17, 2022 | Variant summary: STXBP2 c.49G>A (p.Gly17Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251462 control chromosomes, predominantly at a frequency of 0.0098 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal predicted allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.49G>A in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Familial hemophagocytic lymphohistiocytosis 5 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 02, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 18, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
Sift4G
Benign
T;T;T;T
Polyphen
0.88, 0.93
.;.;P;P
Vest4
0.63, 0.70
MutPred
Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);Gain of MoRF binding (P = 0.0225);
MVP
MPC
0.95
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at