chr19-7640939-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_006949.4(STXBP2):c.365G>A(p.Arg122His) variant causes a missense change. The variant allele was found at a frequency of 0.000423 in 1,614,206 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122C) has been classified as Uncertain significance.
Frequency
Consequence
NM_006949.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP2 | NM_006949.4 | c.365G>A | p.Arg122His | missense_variant | 6/19 | ENST00000221283.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP2 | ENST00000221283.10 | c.365G>A | p.Arg122His | missense_variant | 6/19 | 1 | NM_006949.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00212 AC: 322AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000628 AC: 158AN: 251472Hom.: 1 AF XY: 0.000449 AC XY: 61AN XY: 135914
GnomAD4 exome AF: 0.000244 AC: 357AN: 1461870Hom.: 2 Cov.: 33 AF XY: 0.000205 AC XY: 149AN XY: 727244
GnomAD4 genome AF: 0.00214 AC: 326AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.00187 AC XY: 139AN XY: 74494
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 5 Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 09, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Reported in the heterozygous state in a patient with hemophagocytic lymphohistiocytosis in published literature (Chen et al., 2018) with no second variant identified; This variant is associated with the following publications: (PMID: 29665027, 25556537) - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 29, 2022 | Variant summary: STXBP2 c.365G>A (p.Arg122His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 251472 control chromosomes (gnomAD), predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.365G>A has been reported in the literature in the heterozygous state in a Chinese individual affected with Hemophagocytic Lymphohistiocytosis with no second variant reported (Chen_2018). This does not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, there are no publications with experimental evidence demonstrating an impact on protein function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as benign and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign. - |
STXBP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 11, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Autoinflammatory syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 08, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at