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STAG2c.482T>AUncertain significance
Print report
Variant interpretation report

STAG2 c.482T>A, p.(Leu161His)

NM_001042749.1:c.482T>A NP_001036214.1:p.(Leu161His) 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
PM2Moderate
PM2 · moderate

Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% allele frequency in large population databases. Note: STAG2 is located on the X chromosome; absence from gnomAD should be interpreted with awareness of potentially reduced X-chromosome coverage in some regions.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product or splicing. SpliceAI predicts no significant splice impact (max delta score 0.01), and BayesDel score is 0.086 (low, consistent with a benign effect on protein function). Two independent in silico tools support a neutral or benign interpretation.

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 moderate, BP4 supporting benign; combination = 1 moderate + 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.

29 criteria with recorded statuses: 2 met · 19 not met · 4 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001042749.1:c.482T>A (p.Leu161His) in STAG2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength, though X-chromosome coverage caveats apply.

SpliceAI predicts no splice impact (max delta 0.01) and BayesDel score is 0.0859 (low/benign range), meeting BP4 at supporting benign strength.

This variant is absent from ClinVar and COSMIC and has not been reported in the literature; no functional, segregation, or case-control data are available for variant-specific assessment.

With 1 moderate pathogenic criterion (PM2) and 1 supporting benign criterion (BP4), this variant does not meet the threshold for Likely Pathogenic or Likely Benign under generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 ModerateAbsent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% allele frequency in large population databases. Note: STAG2 is located on the X chromosome; absence from gnomAD should be interpreted with awareness of potentially reduced X-chromosome coverage in some regions. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Still missing
  • X-chromosome coverage at this position not independently verified
  • absence may reflect coverage gap rather than true population absence.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product or splicing. SpliceAI predicts no significant splice impact (max delta score 0.01), and BayesDel score is 0.086 (low, consistent with a benign effect on protein function). Two independent in silico tools support a neutral or benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.01: no splice alteration predicted.
  • BayesDel 0.0858646: score in the low/benign range.
Still missing
  • REVEL score unavailable.
Sources
spliceai ↗bayesdel

Not met · 19 · evaluated, threshold not reached

PVS1 PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon-level deletions) under the ClinGen SVI framework (PMC6185798). This is a missense variant (p.Leu161His) and does not fall into any null-variant bucket. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Leu161His)
  • variant_bucket='other'
  • not eligible for generic PVS1.
Sources
pvs1_generic_framework ↗
PS1 Requires the same amino acid change (p.Leu161His) to have been previously established as pathogenic. This variant is absent from ClinVar and no literature reports this exact amino acid change as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no prior pathogenic classification for p.Leu161His.
Sources
clinvar ↗
PS2 Requires a confirmed de novo observation with both maternity and paternity confirmed. No family or trio data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No family/trio data.
PS3 Requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No variant-specific functional data were identified; OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed evidence. The five reviewed publications provide only gene-level context and none tested this variant experimentally. Details ▾Hide ▴
Evidence considered
  • No functional studies for this variant. OncoKB: Unknown Oncogenic Effect. BayesDel score (0.086) is a computational prediction
  • not experimental functional data.
Still missing
  • No functional characterization of p.Leu161His.
Sources
oncokb ↗
PS4 Requires a statistically higher prevalence of the variant in affected individuals versus controls. This variant is absent from ClinVar and COSMIC; no case-control data are available. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar and COSMIC.
Still missing
  • No case-control data.
Sources
clinvar ↗
PM1 Requires the variant to lie in a mutational hotspot or a well-characterized critical functional domain without benign variation. The residue L161 is not reported as a statistically significant hotspot by cancerhotspots.org, and no literature was identified that characterizes the region around position 161 as a critical functional domain with intolerance to missense variation. Details ▾Hide ▴
Evidence considered
  • Not in a cancerhotspots.org mutational hotspot. No literature characterizing position 161 as part of a critical domain.
Still missing
  • Domain architecture at position 161 not specifically characterized in reviewed literature.
Sources
oncokb ↗
PM5 Requires a different pathogenic missense change at the same residue (Leu161). No same-residue pathogenic comparator variants were identified in ClinVar, and the automated PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator candidates found.
Sources
pm5_candidatesclinvar ↗
PM6 Requires a de novo observation without confirmation of paternity and maternity. No de novo data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No family/trio data.
PP1 Requires cosegregation of the variant with disease in multiple affected family members. No family or segregation data are available. Details ▾Hide ▴
Evidence considered
  • No cosegregation data available.
Still missing
  • No family/segregation data.
PP3 Requires multiple lines of computational evidence to support a deleterious effect on the gene product. SpliceAI predicts no splice impact (max delta 0.01), and BayesDel score is 0.086 (low, consistent with a benign prediction). REVEL is unavailable. The available computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.01 (no splice impact).
  • BayesDel: 0.0858646 (low
  • consistent with benign).
  • REVEL: unavailable.
Still missing
  • REVEL score not available for this variant.
Sources
spliceai ↗bayesdel
PP5 Requires a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory) to have recently reported the variant as pathogenic. The variant is absent from ClinVar with no submissions of any kind. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no reputable source has classified this variant.
Sources
clinvar ↗
BA1 Requires an allele frequency >1% in population databases (non-VCEP rule). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. It does not meet the BA1 frequency threshold. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
  • frequency far below 1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Requires an allele frequency >0.3% in population databases (non-VCEP rule). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. It does not meet the BS1 frequency threshold. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
  • frequency far below 0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 Requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No functional studies have been performed on this variant. BayesDel score (0.086) is a computational prediction and does not qualify as well-established functional evidence. Details ▾Hide ▴
Evidence considered
  • No experimental functional studies available. BayesDel 0.086 and SpliceAI 0.01 are computational
  • not experimental.
Still missing
  • No experimental functional characterization of p.Leu161His.
Sources
bayesdelspliceai ↗
BS4 Requires lack of segregation with disease in affected family members. No family or segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family/segregation data.
BP1 Requires the variant to be a missense change in a gene for which primarily truncating variants cause disease. While some STAG2 disease-associated variants are truncating (PMID:41492387 describes STAG2-truncating variants in germline disease), the literature also describes pathogenic missense STAG2 variants in both somatic and germline contexts. There is insufficient evidence that only truncating variants cause STAG2-related disease. Details ▾Hide ▴
Evidence considered
  • STAG2 disease includes both missense and truncating variants
  • not established as a primarily-truncating-variant disease gene.
BP5 Requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available. Details ▾Hide ▴
Evidence considered
  • No cases with alternate molecular basis identified.
Still missing
  • No alternate-diagnosis data.
BP6 Requires a reputable source to have recently reported the variant as benign. The variant is absent from ClinVar with no submissions of any kind. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification exists.
Sources
clinvar ↗
PS5 Requires a reputable source to have recently attributed pathogenicity to this variant. The variant is absent from ClinVar and no literature reports it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Still missing
  • No source attributes pathogenicity to this variant.
Sources
clinvar ↗

Not assessed · 4 · no assessment recorded

PP2 Requires evidence that STAG2 has a low rate of benign missense variation and that missense variants are a common mechanism of disease. No gene-level constraint metrics (missense Z-score, gnomAD constraint, pLI) were available in the evidence packet, and HCI prior scores were not available for STAG2. Details ▾Hide ▴
Evidence considered
  • No constraint data (Z-score
  • pLI) available for STAG2.
Still missing
  • Need gnomAD gene constraint metrics or equivalent to assess missense intolerance.
PP4 Requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No clinical phenotype or family history was provided for assessment. Details ▾Hide ▴
Evidence considered
  • No patient phenotype provided.
Still missing
  • Patient clinical phenotype and family history not available.
BS2 Requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age. No individual-level phenotype data are available for any carriers, and no carriers were identified in population databases. Details ▾Hide ▴
Evidence considered
  • No carrier phenotype data available.
Still missing
  • No individual-level carrier data to assess.
BP2 Requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a known pathogenic variant. No phase data are available. Details ▾Hide ▴
Evidence considered
  • No phase data available.
Still missing
  • No phase data.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to recessive disorders (variant detected in trans with a pathogenic variant); STAG2-related disease is not established as recessive and no phase data available. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length changes from non-frameshift indels or stop-loss variants; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in non-repetitive regions; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Leu161His) and does not qualify. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
STAG2
Transcript
NM_001042749.1
Coding (HGVS c.)
NM_001042749.1:c.482T>A
Protein (HGVS p.)
NP_001036214.1:p.(Leu161His)
GRCh38
chrX:124045183 T>A
GRCh37
chrX:123179033 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 +135 bp
0.010
SpliceAI acceptor gainat -14 bp
0.010
SpliceAI donor lossat -128 bp
0.010
SpliceAI donor gainat +60 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.086

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product or splicing. SpliceAI predicts no significant splice impact (max delta score 0.01), and BayesDel score is 0.086 (low, consistent with a benign effect on protein function). Two independent in silico tools support a neutral or benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.01: no splice alteration predicted.
  • BayesDel 0.0858646: score in the low/benign range.
Still missing
  • REVEL score unavailable.
Sources
spliceai ↗bayesdel
PP3 Requires multiple lines of computational evidence to support a deleterious effect on the gene product. SpliceAI predicts no splice impact (max delta 0.01), and BayesDel score is 0.086 (low, consistent with a benign prediction). REVEL is unavailable. The available computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.01 (no splice impact).
  • BayesDel: 0.0858646 (low
  • consistent with benign).
  • REVEL: unavailable.
Still missing
  • REVEL score not available for this variant.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Leu161His) and does not qualify. 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 = 0.0858646.

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 = 0.0858646.

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.