NM_001042749.1:c.488T>A

STAG2 · NP_001036214.1:p.(Met163Lys) · NM_001042749.1

GRCh37: chrX:123179039 T>A · GRCh38: chrX:124045189 T>A

Gene: STAG2 Transcript: NM_001042749.1

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

STAG2

Transcript

NM_001042749.1

Protein

NP_001036214.1:p.(Met163Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001042749.1:c.488T>A (p.Met163Lys) in STAG2 is a missense variant absent from population databases (PM2_Supporting).

Multiple in silico predictors (BayesDel = -0.143, SpliceAI max delta = 0.01) suggest no significant impact on protein function or splicing (BP4_Supporting).

This variant is absent from ClinVar, has no published functional data, and has not been reported in any disease cohort. The variant is not a null variant type (PVS1 not met) and does not reside in a mutational hotspot (PM1 not met).

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification beyond a variant of uncertain significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Not met	NM_001042749.1:c.488T>A is a missense variant (p.Met163Lys) and does not fall into the ClinGen PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the generic PVS1 decision framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic or likely pathogenic variant with the same amino acid change (p.Met163Lys) has been reported in ClinVar or the literature. PS1 requires a previously established pathogenic variant resulting in the identical amino acid substitution, which is not available for this variant.	clinvar
PS2	Not assessed	No de novo data are available for this variant. Parental testing status is unknown.
PS3	Not met	No functional studies have tested NM_001042749.1:c.488T>A or a systematically characterized range that includes p.Met163. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No COSMIC entries exist. PS3 requires experimental functional data demonstrating a damaging effect.	oncokb
PS4	Not assessed	No case-control or patient cohort prevalence data are available for this variant. The variant is absent from ClinVar and population databases, providing no opportunity to assess enrichment in affected individuals.
PS5	Not met	PS5 requires a different pathogenic missense change at the same residue established through functional data. No alternative pathogenic variant at p.Met163 has been identified in ClinVar or the literature.	clinvar pm5_candidates
PM1	Not met	The variant p.Met163Lys does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative) and no literature establishes a well-characterized critical functional domain encompassing position 163. While STAG2 encodes a cohesin complex component, domain-level PM1 requires a specific functional domain with defined boundaries that includes this residue, for which no citation is available.
PM2	Met	NM_001042749.1:c.488T>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele count = 0 in all datasets). The variant has not been observed in population reference databases, meeting the PM2 threshold for a rare variant (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic or likely pathogenic missense variant at the same amino acid residue (p.Met163) with a different alteration has been identified. Automated PM5 candidate harvesting returned zero comparators. PM5 cannot be applied without a qualifying comparator variant.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant. Assumed de novo without confirmation of paternity and maternity cannot be applied without supporting evidence.
PP1	Not assessed	No cosegregation data are available. Family studies have not been performed or reported for this variant.
PP2	Not assessed	HCI prior scores are not available for STAG2 (gene not supported in the HCI database). Without a gene-specific missense constraint metric (z-score) or HCI prior probability, PP2 cannot be reliably assessed.
PP3	Not met	Multiple in silico tools predict no significant impact. BayesDel score is -0.143023 (benign range). SpliceAI max delta score is 0.01, predicting no splicing effect. REVEL score is unavailable for this variant. Computational evidence does not support a deleterious effect; instead, predictions trend benign.	bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for review. The variant was submitted for interpretation without accompanying clinical information.
PP5	Not met	NM_001042749.1:c.488T>A is absent from ClinVar. No reputable source has classified this variant as pathogenic. PP5 requires a pathogenic assertion from a trusted clinical laboratory or expert panel.	clinvar
BA1	Not met	NM_001042749.1:c.488T>A is absent from all population databases (gnomAD v2.1, v4.1, and Canada; allele count = 0). The allele frequency is 0%, far below the BA1 threshold of >5% (or >1% per non-VCEP standards). This variant does not meet the stand-alone benign frequency criterion.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_001042749.1:c.488T>A is absent from all population databases. The allele frequency is 0%, far below the BS1 threshold of >0.3% for a rare disease variant under non-VCEP standards. The variant is too rare to satisfy BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults. BS2 requires documentation of the variant in a healthy individual inconsistent with disease penetrance, which cannot be assessed without clinical context.
BS3	Not met	No well-established functional studies demonstrate a neutral or benign effect for this variant. BS3 requires experimental evidence showing no deleterious effect on protein function or splicing. In silico predictions (addressed under BP4) do not constitute BS3-level evidence.
BS4	Not assessed	No segregation data are available for this variant. BS4 requires observation of non-segregation with disease in affected families, which is not available.
BP1	Not met	BP1 requires that the gene primarily causes disease through a truncating mechanism and that missense variants are an uncommon cause of disease. STAG2 is associated with disease through both missense and truncating variants in cohesinopathies and myeloid malignancies. The literature supports both missense and truncating pathogenic variants in STAG2, so BP1 does not apply.
BP2	Not assessed	No data are available on whether this variant has been observed in trans with a known pathogenic variant. BP2 cannot be assessed without phase information.
BP4	Met	Multiple lines of computational evidence predict no significant impact on the gene product. BayesDel score is -0.143023 (benign), and SpliceAI predicts no splicing effect (max delta score = 0.01). Two independent in silico predictors agree on a neutral/benign effect, meeting BP4 at supporting strength.	bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternative molecular basis for disease in the proband. BP5 requires identification of a different causative variant that explains the phenotype.
BP6	Not met	NM_001042749.1:c.488T>A is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. BP6 requires a benign assertion from a trusted clinical laboratory or expert panel.	clinvar
BP7	N/A	NM_001042749.1:c.488T>A is a missense variant (p.Met163Lys), not a synonymous/silent variant. BP7 is restricted to synonymous variants with no predicted splice impact.

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