Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001042749.2 | Alternative | 6342 nt | 470–4276 |
| NM_001042749.1 | Alternative | 6277 nt | 405–4211 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The STAG2 I794Nfs*15 variant is a truncating mutation in a tumor suppressor gene, leading to likely loss of function. Functional studies indicate that truncating mutations in STAG2 result in loss of protein expression, likely due to nonsense-mediated mRNA decay. Depletion of STAG2 in certain cancer cell lines causes significant chromosomal abnormalities, highlighting its role in maintaining chromosomal stability. Correction of STAG2 aberrations in glioblastoma cell lines restores sister chromatid cohesion and reduces chromosomal instability. However, in AML patients, STAG2 truncating mutations do not lead to chromosomal aberrations, and patients maintain a normal karyotype. Overall, the functional evidence supports a damaging effect of the STAG2 I794Nfs*15 variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 18 bp |
| Donor Loss (DL) | 0.01 | 154 bp |
| Acceptor Gain (AG) | 0.02 | -445 bp |
| Donor Gain (DG) | 0.0 | -368 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: NM_001042749.1:c.2380dupA is a frameshift leading to a premature stop (I794Nfs*15) in STAG2, a gene where LoF is an established disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant clearly results in loss of function in a LoF gene.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: there is no previously reported variant with the same amino acid change. Therefore, this criterion is not applied because no such variant exists.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: de novo status has not been evaluated. Therefore, this criterion is not applied because there is no de novo evidence.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: functional studies demonstrate that truncating STAG2 variants lead to loss of protein via nonsense-mediated decay, cause chromosomal instability in cell lines, and that correction restores cohesion. Therefore, this criterion is applied at Strong strength because multiple well-established studies show a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied because comparative prevalence data are lacking.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: exon/domain information is unavailable. Therefore, this criterion is not applied because hotspot or domain localization cannot be determined.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: it is not present in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because it is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no information on compound heterozygosity. Therefore, this criterion is not applied because trans configuration data are absent.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a frameshift leading to truncation, not an in-frame change. Therefore, this criterion is not applied because the variant type is not in-frame.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied because it is not a novel missense variant.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: de novo status is not assessed. Therefore, this criterion is not applied because there is no assumed de novo evidence.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied because family segregation has not been studied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied because it is not a missense variant.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: limited in silico data and the variant is truncating. Therefore, this criterion is not applied because computational evidence is not the primary driver for a null variant.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or family history information provided. Therefore, this criterion is not applied because phenotype specificity cannot be assessed.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no such reports in ClinVar or other databases. Therefore, this criterion is not applied because no reputable source cites it as pathogenic.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied because the allele frequency is not high.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: it is absent from databases. Therefore, this criterion is not applied because frequency is not elevated.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no data on occurrence in healthy individuals. Therefore, this criterion is not applied because BS2 conditions are not met.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: functional studies support damaging effect. Therefore, this criterion is not applied because the functional evidence is the opposite.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: segregation data are not available. Therefore, this criterion is not applied because segregation has not been assessed.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: it is a LoF variant. Therefore, this criterion is not applied because it is not a missense change.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant'. The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied because cis/trans information is unavailable.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function'. The evidence for this variant shows: it is a frameshift, not in-frame. Therefore, this criterion is not applied because the variant is not in-frame.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: it is a null variant, and computational evidence is secondary. Therefore, this criterion is not applied because computational predictions are not meaningful for a truncating lesion.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such cases reported. Therefore, this criterion is not applied because no alternate molecular basis is described.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no reputable source reports benign status. Therefore, this criterion is not applied because no such report exists.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied because it is a frameshift variant.