rs758554274
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_006949.4(STXBP2):c.1672G>A(p.Glu558Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,604,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E558D) has been classified as Uncertain significance.
Frequency
Consequence
NM_006949.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP2 | NM_006949.4 | c.1672G>A | p.Glu558Lys | missense_variant | 18/19 | ENST00000221283.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP2 | ENST00000221283.10 | c.1672G>A | p.Glu558Lys | missense_variant | 18/19 | 1 | NM_006949.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000869 AC: 2AN: 230252Hom.: 0 AF XY: 0.00000798 AC XY: 1AN XY: 125360
GnomAD4 exome AF: 0.0000248 AC: 36AN: 1452746Hom.: 0 Cov.: 76 AF XY: 0.0000249 AC XY: 18AN XY: 722242
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74340
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 558 of the STXBP2 protein (p.Glu558Lys). This variant is present in population databases (rs758554274, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with STXBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 330563). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at