NM_001042749.1:c.1018-1G>A

STAG2 · NP_001036214.1:p.? · NM_001042749.1

GRCh37: chrX:123184970 G>A · GRCh38: chrX:124051120 G>A

Gene: STAG2 Transcript: NM_001042749.1

Final call

Pathogenic

PVS1 very strong PM2 moderate PP5 supporting

Variant details

Gene

STAG2

Transcript

NM_001042749.1

Protein

NP_001036214.1:p.?

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001042749.1:c.1018-1G>A is a canonical splice acceptor variant in STAG2, where loss of function is a known disease mechanism. The variant is assigned PVS1 at very strong strength under ClinGen SVI PVS1 recommendations (PMC6185798), supported by SpliceAI delta 1.00 predicting abolition of the canonical 3' acceptor site.

This variant is completely absent from gnomAD v2.1 and v4.1 (0/506,187 alleles across all populations), meeting PM2 at moderate strength.

The variant has been reported as Pathogenic in ClinVar (Variation ID: 3339587) by a reputable clinical diagnostic laboratory (LabCorp, SCV005204398), meeting PP5 at supporting strength.

No variant-specific functional data, de novo observations, segregation data, or case-control prevalence data were identified in any reviewed publication. All six ClinVar-cited PMIDs discuss STAG2 and cohesin mutations at the gene level in myeloid malignancies without mentioning NM_001042749.1:c.1018-1G>A.

The combination of 1 very strong (PVS1), 1 moderate (PM2), and 1 supporting (PP5) criterion meets the generic ACMG/AMP 2015 threshold for Pathogenic classification under the rule: 1 Very Strong + 1 Moderate + ≥1 Supporting.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	NM_001042749.1:c.1018-1G>A is a canonical splice acceptor variant (c.1018-1G>A, intron 11) predicted to disrupt normal splicing with SpliceAI delta score 1.00 (acceptor loss 1.0). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants are eligible for PVS1 at very strong strength when loss of function is an established disease mechanism for the gene. STAG2 germline LoF mechanism is supported by targeted literature review identifying multiple publications linking STAG2 loss of function to human disease.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Splice variant with no amino acid change; no same-amino-acid-change comparator applicable.
PS2	Not assessed	No de novo data available for this variant in any reviewed source.
PS3	Not met	No variant-specific functional data identified. All six ClinVar-cited publications discuss STAG2 and cohesin complex mutations at the gene level in myeloid malignancies; none directly tested or reported functional data for NM_001042749.1:c.1018-1G>A. The ClinVar submitter themselves noted that functional studies have yet to be confirmed.
PS4	Not assessed	Insufficient variant-specific prevalence data in affected individuals. The variant is reported once in ClinVar (single submitter) and once somatically in COSMIC; no case-control or cohort prevalence data are available.
PS5	N/A	Splice variant; no missense comparator applicable at the same position.
PM1	Not met	No mutational hotspot at this position. The variant is a splice site disruption (c.1018-1G>A) and does not reside within a characterized functional domain residue. No residue-specific hotspot was identified in cancerhotspots.org, and no domain-level clustering of pathogenic variants was established for this specific splice junction.
PM2	Met	This variant is completely absent from gnomAD v2.1 and v4.1 (0/506,187 alleles across all populations). Allele frequency of 0% is well below the 0.1% PM2 threshold in all subpopulations, including the highest-observed African/African American population (0/30,346 alleles).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to resolve missense residue context from the normalized protein consequence (NP_001036214.1:p.?). No same-residue comparator variants could be identified for PM5 evaluation.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant in any reviewed source.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	N/A	Splice variant, not a missense change. PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	N/A	Per ClinGen SVI PVS1 recommendations (PMC6185798), splice prediction evidence (SpliceAI delta 1.00) should not be double-counted with PVS1 for canonical splice variants. The deleterious splice prediction is already captured by PVS1 at very strong strength.	pvs1_variant_assessment spliceai
PP4	Not assessed	No variant-specific phenotype or family history data available. The variant is listed under STAG2-Related Disorders in ClinVar without specific phenotypic detail.	clinvar
PP5	Met	This variant has been reported as Pathogenic in ClinVar (Variation ID: 3339587) by Women's Health and Genetics/Laboratory Corporation of America, LabCorp (SCV005204398), a reputable clinical diagnostic laboratory. Although the submission is from a single submitter with criteria provided, the classification from a CLIA-certified laboratory constitutes a reputable source report under ACMG/AMP PP5.	clinvar
BA1	Not met	Allele frequency is 0% in gnomAD v4.1 (0/506,187 alleles), far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Allele frequency is 0% in gnomAD v4.1, far below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adult individuals available.
BS3	Not assessed	No functional studies demonstrating a benign or neutral effect for this variant exist in the available literature. The six ClinVar-cited publications provide only gene-level context without variant-specific functional data.
BS4	Not assessed	No cosegregation data available to assess lack of segregation with disease.
BP1	N/A	Splice variant, not a missense variant. BP1 applies only to missense variants in genes where a truncating mechanism is primarily causative.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant.
BP3	N/A	Skipped per user directive: splice variant, not an in-frame indel in a repetitive region.
BP4	Not met	Multiple lines of computational evidence predict a deleterious effect. SpliceAI predicts strong splice disruption (max delta 1.00; acceptor loss 1.0, acceptor gain 0.8). BayesDel score is 0.297619, which is below commonly used deleterious thresholds for missense variants but not directly informative for splice variants. Computational evidence does not support a benign interpretation.	spliceai bayesdel
BP5	Not assessed	No data on an alternate molecular cause for the phenotype in a case harboring this variant.
BP6	Not met	ClinVar reports this variant as Pathogenic (Variation ID: 3339587), not as benign. BP6 requires a reputable source reporting the variant as benign or likely benign.	clinvar
BP7	Not met	This is a canonical splice acceptor variant (c.1018-1G>A) with SpliceAI max delta 1.00, predicting strong splice disruption. The variant directly alters a consensus splice site, which is the opposite of the BP7 requirement for a silent intronic variant with no predicted splice impact.	spliceai

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