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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -31 bp |
| Donor Loss (DL) | 0.0 | -147 bp |
| Acceptor Gain (AG) | 0.01 | 168 bp |
| Donor Gain (DG) | 0.0 | 246 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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: it is a missense change (A350V), not a null variant. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but a different nucleotide change". The evidence for this variant shows: no previously established pathogenic variant causes A350V in STAG2. Therefore, this criterion is not applied because there is no known pathogenic variant with the same amino acid change.
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 assessed or confirmed. Therefore, this criterion is not applied because there is no confirmed de novo occurrence.
PS3 (Not Applied)
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: no functional studies have been performed on STAG2 A350V. Therefore, this criterion is not applied because functional data are lacking.
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 in affected cohorts. Therefore, this criterion is not applied because there is no statistical enrichment evidence.
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: no information that A350 lies in a known hot spot or critical functional domain. Therefore, this criterion is not applied due to lack of domain-specific evidence.
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 absent from gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is not observed in large control populations.
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 phase or trans observations. Therefore, this criterion is not applied because trans configuration data are unavailable.
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 missense substitution without protein length alteration. Therefore, this criterion is not applied because there is no protein length change.
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: no other pathogenic missense changes reported at residue A350. Therefore, this criterion is not applied due to absence of precedent.
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: no de novo assessment. Therefore, this criterion is not applied because there is no assumption of de novo without confirmation.
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 due to lack of family segregation information.
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: insufficient data on STAG2 missense variation rates and disease mechanism. Therefore, this criterion is not applied because gene-specific missense intolerance is not established.
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 (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico predictions are mixed with some tools benign (CADD=5.29, REVEL=0.21) and SpliceAI no impact. Therefore, this criterion is not applied due to lack of consistent computational support for deleterious effect.
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 clinical 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: not present in ClinVar or other reputable sources. Therefore, this criterion is not applied due to absence of external pathogenic assertions.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: allele frequency is 0%, not high. Therefore, this criterion is not applied because the variant is not common enough.
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: allele frequency is 0%, below any threshold. Therefore, this criterion is not applied due to lack of elevated population frequency.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied because healthy cohort data are not available.
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: no functional studies have been conducted. Therefore, this criterion is not applied due to absence of functional evidence.
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: no family segregation data. 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: STAG2 disease mechanism is not established as exclusively LoF. Therefore, this criterion is not applied because gene mechanism is unclear.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no information on cis or trans with other variants. Therefore, this criterion is not applied due to lack of variant phase data.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied because the variant type does not match BP3.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact)". The evidence for this variant shows: in silico predictions are mixed but overall support benign (REVEL=0.21, CADD=5.29, SpliceAI=0.01). Therefore, this criterion is applied at Supporting strength because computational data favor no functional impact.
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 case reports with alternate etiology. Therefore, this criterion is not applied because no such case data exist.
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 benign assertions in databases. Therefore, this criterion is not applied because no external benign reports are available.
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 a missense change (A350V), not synonymous. Therefore, this criterion is not applied because the variant is not synonymous.