19-7647436-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_006949.4(STXBP2):c.1621G>T(p.Gly541Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G541S) has been classified as Pathogenic.
Frequency
Consequence
NM_006949.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STXBP2 | ENST00000221283.10 | c.1621G>T | p.Gly541Cys | missense_variant | 18/19 | 1 | NM_006949.4 | ENSP00000221283.4 | ||
ENSG00000268400 | ENST00000698368.1 | n.*1724G>T | non_coding_transcript_exon_variant | 20/20 | ENSP00000513686.1 | |||||
ENSG00000268400 | ENST00000698368.1 | n.*1724G>T | 3_prime_UTR_variant | 20/20 | ENSP00000513686.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248156Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134664
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461152Hom.: 0 Cov.: 77 AF XY: 0.00000275 AC XY: 2AN XY: 726882
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 13, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 541 of the STXBP2 protein (p.Gly541Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 969042). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Gly541 amino acid residue in STXBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20558610, 20798128, 20823128, 23687090, 24194549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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