STAG2 c.993delinsGGAAAGC, p.Tyr331Ter
NM_001042749.1:c.993delinsGGAAAGC
Pathogenic
This variant is classified as Pathogenic based on a Very Strong PVS1 null effect, Strong PS3 functional evidence, and Moderate PM2 absence from controls. The combined evidence supports a loss-of-function mechanism consistent with disease.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
STAG2
Transcript
NM_001042749.2
Total Exons
35
Strand
Forward (+)
Reference Sequence
NC_000023.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001042749.1 | Alternative | 35 exons | Forward |
Variant Details
HGVS Notation
NM_001042749.1:c.993delinsGGAAAGC
Protein Change
Y331*
Location
Exon 11
(Exon 11 of 35)
5'Exon Structure (35 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001042749.2
Genome Browser
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HGVS InputNM_001042749:c.993delinsGGAAAGC
Active Tracks
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The STAG2 Y331* variant is a truncating mutation that likely results in loss of protein expression due to nonsense-mediated mRNA decay. Functional studies indicate that depletion of STAG2 leads to significant chromosomal abnormalities, highlighting its role in maintaining chromosomal stability. Correction of STAG2 aberrations in glioblastoma cell lines has been shown to restore sister chromatid cohesion and reduce chromosomal instability. However, in AML patients, STAG2 truncating mutations do not result in chromosomal aberrations, suggesting context-dependent effects. Overall, the functional evidence supports a damaging effect of the STAG2 Y331* variant in certain contexts.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LoF) is a known mechanism of disease." The evidence for this variant shows: NM_001042749.1:c.993delinsGGAAAGC results in Y331* truncation expected to undergo nonsense-mediated mRNA decay, leading to loss of STAG2 function. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where LoF is a known disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change." The evidence for this variant shows: no known pathogenic variant at amino acid position Y331 reported. Therefore, this criterion is not applied because there is no prior pathogenic variant causing the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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: no data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo confirmation data.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: functional studies demonstrate that STAG2 truncation leads to chromosomal instability and that restoration of STAG2 rescues sister chromatid cohesion. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PS4 is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case-control or statistical correlation data available. Therefore, this criterion is not applied due to absence of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: transcript exon structure and functional domain annotation unavailable, so hotspot/domain location cannot be determined. Therefore, this criterion is not applied due to inability to assess domain context.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: the variant is not observed in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because it is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: no data on allelic phase or trans configuration. Therefore, this criterion is not applied due to lack of trans configuration data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a nonsense/truncating variant rather than an in-frame change or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before." The evidence for this variant shows: it introduces a stop codon (nonsense), not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no data on assumed de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PP1 is: "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease." The evidence for this variant shows: it is a truncating variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: in silico tools (e.g., SpliceAI) predict minimal splicing impact and computational algorithms provide no support for a benign mechanism. However, the variant is truncating and computational tools for nonsenses are not informative. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule PP5 is: "Reputable source reports variant as pathogenic but without available evidence." The evidence for this variant shows: no entries in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BA1 is: "Allele frequency is too high for the disorder." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BS1 is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BS2 is: "Observed in healthy individuals 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.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: functional studies demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BP1 is: "Missense variant in a gene where only loss of function causes disease." The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant." The evidence for this variant shows: no evidence of cis/trans configuration. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift/nonsense, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: truncation clearly impacts the protein; computational tools are not informative for nonsense variants. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule BP6 is: "Reputable source reports variant as benign but without evidence." The evidence for this variant shows: no benign reports in ClinVar or literature. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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.