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STAG2c.488T>AUncertain significance
Print report
Variant interpretation report

STAG2 c.488T>A, p.(Met163Lys)

NM_001042749.1:c.488T>A NP_001036214.1:p.(Met163Lys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About STAG2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. STAG2, a component of the cohesin complex, is recurrently altered by mutation in various cancer types.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 13 not met · 10 not assessed · 1 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 SupportingNM_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%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (AC=0)
  • gnomAD v4.1: absent (AC=0)
  • gnomAD-Canada v1.0: absent (AC=0
  • AF=0.0)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.143023 (benign prediction)
  • SpliceAI: max delta 0.01 (no splice alteration predicted)
Sources
bayesdelspliceai ↗

Not met · 13 · evaluated, threshold not reached

PVS1 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). Details ▾Hide ▴
Evidence considered
  • Variant classified as missense (p.Met163Lys)
  • variant_bucket='other'
  • No canonical splice consensus disruption
  • Gene-level PVS1 gate is eligible (STAG2 LoF supported as germline disease mechanism)
  • but variant does not meet null-variant criteria
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries for NM_001042749.1:c.488T>A or any variant at p.Met163
  • No publications reporting a pathogenic p.Met163Lys change
Sources
clinvar ↗
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence
  • COSMIC: variant not reported in somatic cancers
  • No publications with functional assays testing p.Met163Lys or a characterized range including this residue
Still missing
  • No functional studies available for this variant
Sources
oncokb ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • CancerHotspots: residue not significant
  • exact variant not listed
  • No literature establishing a critical functional domain including p.Met163
Still missing
  • No domain-level evidence for position 163
PM5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates
  • No ClinVar entries with an alternative amino acid change at position 163
Still missing
  • No comparator variant at the same residue
Sources
pm5_candidates
PP3 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.143023 (negative/benign)
  • SpliceAI: max delta 0.01 (no splice impact)
  • REVEL: not available for this variant
Sources
bayesdelspliceai ↗
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries found
  • variant is absent from the database
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada: AC=0
  • AF=0.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada: AC=0
  • AF=0.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: no functional evidence available
  • No publications with functional assays for this variant
Still missing
  • No well-established functional studies testing this variant
BP1 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. Details ▾Hide ▴
Evidence considered
  • STAG2 disease mechanism includes both missense and truncating variants
  • Cohesinopathies (holoprosencephaly
  • CdLS-like phenotypes) involve both variant types
BP6 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries found for this variant
Sources
clinvar ↗
PS5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no variants at amino acid position 163
  • PM5 candidate search returned zero comparators at this residue
Still missing
  • No functionally characterized alternative changes at p.Met163
Sources
clinvar ↗pm5_candidates

Not assessed · 10 · no assessment recorded

PS2 No de novo data are available for this variant. Parental testing status is unknown. Details ▾Hide ▴
Still missing
  • No parental genotype data available
  • No de novo reports in ClinVar or literature
PS4 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. Details ▾Hide ▴
Still missing
  • No patient cohort data
  • No case-control studies
PM6 No de novo data are available for this variant. Assumed de novo without confirmation of paternity and maternity cannot be applied without supporting evidence. Details ▾Hide ▴
Still missing
  • No de novo reports in ClinVar or literature
  • No parental testing data
PP1 No cosegregation data are available. Family studies have not been performed or reported for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported for STAG2
Still missing
  • No missense constraint data (HCI prior or z-score unavailable for STAG2)
PP4 No patient phenotype or clinical data are available for review. The variant was submitted for interpretation without accompanying clinical information. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided
BS2 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. Details ▾Hide ▴
Still missing
  • No data on variant presence in healthy adult controls
BS4 No segregation data are available for this variant. BS4 requires observation of non-segregation with disease in affected families, which is not available. Details ▾Hide ▴
Still missing
  • No family segregation data to assess non-segregation
BP2 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. Details ▾Hide ▴
Still missing
  • No trans phase data with pathogenic variants
BP5 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. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data
Not applicable · 1· recorded as not applicable Show reasons ▾Hide reasons ▴
BP7 N/ANM_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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
STAG2
Transcript
NM_001042749.1
Coding (HGVS c.)
NM_001042749.1:c.488T>A
Protein (HGVS p.)
NP_001036214.1:p.(Met163Lys)
GRCh38
chrX:124045189 T>A
GRCh37
chrX:123179039 T>A

Gene diagram

Every interpreted variant in STAG2, mapped onto the exon structure of NM_001042749.1. Select a row to find it on the plot.

STAG2NM_001042749.1
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -25 bp
0.000
SpliceAI acceptor gainat +129 bp
0.010
SpliceAI donor lossat -134 bp
0.000
SpliceAI donor gainat +54 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
-0.143

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.143023 (benign prediction)
  • SpliceAI: max delta 0.01 (no splice alteration predicted)
Sources
bayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.143023 (negative/benign)
  • SpliceAI: max delta 0.01 (no splice impact)
  • REVEL: not available for this variant
Sources
bayesdelspliceai ↗
BP7 N/ANM_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. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.143023.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.143023.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. STAG2, a component of the cohesin complex, is recurrently altered by mutation in various cancer types.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.