STAG2 c.3378dup, p.Arg1127GlufsTer9
NM_001042749.1:c.3378dup
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.3378dup
Protein Change
R1127Efs*9
Location
Exon 31
(Exon 31 of 35)
5'
Exon Structure (35 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1127 in gene STAG2
Variant interpretation based on transcript NM_001042749.2
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
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
No evidence of other pathogenic variants at position 1127 in gene STAG2
Functional Studies
Summary
The STAG2 R1127Efs*9 variant is a truncating mutation in the tumor suppressor gene STAG2. Functional evidence indicates that truncating mutations in STAG2 lead to loss of protein expression, likely due to nonsense-mediated mRNA decay. Depletion of STAG2 in cell lines results in 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 result in chromosomal aberrations, and patients maintain a normal karyotype. Overall, the functional evidence supports a damaging effect of the STAG2 R1127Efs*9 variant.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
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.3378dup causes a frameshift resulting in a premature stop codon (R1127Efs*9) predicted to trigger nonsense-mediated mRNA decay and loss of STAG2 function. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a gene with a known LoF disease mechanism.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: R1127Efs*9 is novel and does not produce the same amino acid change as any known pathogenic STAG2 variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no information on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: in vitro and in vivo studies demonstrate that STAG2 truncating mutations lead to loss of protein expression, chromosomal instability in cell lines, and restoration of cohesion upon correction. 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 for PS4 is: "PS4 – 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.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no information that R1127 lies in a mutational hotspot or specific functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: not found in population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: STAG2-related disease is not recessive and no trans observations reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: this is a frameshift leading to premature stop, not an in-frame length change or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – 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 a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". 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 for PP2 is: "PP2 – 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: this is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational tools assess splicing impact only and predict minimal effect, which is not relevant to a frameshift LoF. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no detailed phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported 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 for BA1 is: "BA1 – Allele frequency is too high for the disorder". The evidence for this variant shows: absent from population databases, not high frequency. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: absent from controls, not above expected frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – 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 for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – Lack of segregation in affected family members". The evidence for this variant shows: segregation data unavailable. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: this is a LoF variant, not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: this is a frameshift, not an in-frame event. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational tools predict minimal splicing impact but do not address the frameshift LoF. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no benign assertions in reputable sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.