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GNA11c.892C>TUncertain significance
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Variant interpretation report

GNA11 c.892C>T, p.(Pro298Ser)

NM_002067.5:c.892C>T NP_002058.2:p.(Pro298Ser) 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 GNA11

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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

NM_002067.5:c.892C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0%). Meets PM2 threshold (<0.1% in population databases) under generic ACMG/AMP 2015 criteria.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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; combination = 1 moderate, 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied 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. GNA11, a G protein subunit, is recurrently mutated in uveal melanoma.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV50138421, n = 3 times).

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: 1 met · 21 not met · 1 not assessed · 3 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_002067.5:c.892C>T (p.Pro298Ser) in GNA11 is a missense variant absent from gnomAD population databases (PM2).

The variant has been observed in COSMIC (COSV50138421, n=3) in somatic cancers but is absent from ClinVar with no germline classification available.

In silico predictors are conflicting: REVEL score 0.535 is borderline damaging while BayesDel score -0.247 is benign; SpliceAI predicts no splicing impact (max delta 0.00). Neither PP3 nor BP4 is met.

No functional studies, segregation data, de novo reports, or phenotype-specific evidence were identified for this variant.

With only PM2 (moderate) met and no supporting pathogenic or benign criteria, the variant does not meet any ACMG/AMP classification combination and defaults to Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.

Met · 1

PM2 ModerateNM_002067.5:c.892C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0%). Meets PM2 threshold (<0.1% in population databases) under generic ACMG/AMP 2015 criteria. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AC=0).
  • Absent from gnomAD v4.1 (AC=0).
  • Absent from gnomAD-Canada v1.0 (AC=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 No previously established pathogenic variant at amino acid position 298 has been identified. The variant is absent from ClinVar and no same-residue comparator with an established pathogenic classification was found. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no pathogenic comparator at Pro298 identified in PM5 candidate search.
Still missing
  • No same-amino-acid pathogenic variant available for comparison.
Sources
clinvar ↗pm5_candidates
PS2 No de novo data available for this variant. No publications with de novo confirmation of NM_002067.5:c.892C>T were identified. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in case materials or literature.
Still missing
  • No parental testing or de novo data available.
PS3 No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect for P298S. No publications with experimental functional data for NM_002067.5:c.892C>T were found in the case materials. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no reviewed functional evidence. No publications with variant-specific functional assays identified.
Still missing
  • No functional studies of p.Pro298Ser in GNA11 have been identified.
Sources
oncokb ↗
PS4 No case-control or prevalence data available. The variant has been observed in COSMIC (somatic, n=3) but no germline case data with statistical comparison to controls was identified. Details ▾Hide ▴
Evidence considered
  • COSMIC: COSV50138421
  • somatic count 3
  • no germline prevalence data.
Still missing
  • No case-control or cohort study data for this variant in germline context.
PM1 Position 298 is not a statistically significant mutational hotspot per cancerhotspots.org. No domain-level functional evidence specific to the Pro298 residue was identified in the case materials. GNA11 has well-characterized gain-of-function hotspots at R183 and Q209, but P298 is not among the established critical residues. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue not significant. No domain-level evidence for Pro298 in case materials.
Still missing
  • No domain-level functional characterization of GNA11 Pro298 residue identified.
PM6 No de novo data available for NM_002067.5:c.892C>T. No publications reporting de novo occurrence were identified. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in case materials or literature.
Still missing
  • No parental testing or de novo confirmation data available.
PP1 No co-segregation data available. No family studies or pedigrees with this variant were identified. Details ▾Hide ▴
Evidence considered
  • No co-segregation data found in case materials.
Still missing
  • No family studies or segregation data available.
PP3 In silico predictors are conflicting: REVEL 0.535 (borderline damaging, just above 0.5 threshold), BayesDel -0.247 (benign), SpliceAI max delta 0.00 (no splicing impact). Multiple lines of computational evidence do not consistently support a deleterious effect; the conflicting data does not satisfy PP3 requirements. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.535 (borderline).
  • BayesDel: -0.247 (benign).
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype data available to assess whether the clinical presentation is specific for a GNA11-related disorder. No case-level phenotypic information was provided. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data in case materials.
Still missing
  • No phenotypic data for the proband.
PP5 Absent from ClinVar. No 3-star expert panel or other reputable source has classified NM_002067.5:c.892C>T as pathogenic. PP5 default supporting strength cannot be applied without a ClinVar entry meeting the review status threshold. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no expert panel classification available.
Still missing
  • No ClinVar entry exists for this variant.
Sources
clinvar ↗
BA1 Allele frequency is 0% in gnomAD (v2.1, v4.1, Canada), well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0%.
  • gnomAD v4.1: AF=0%.
  • gnomAD-Canada: AF=0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Allele frequency is 0% in gnomAD, below the BS1 threshold of >0.3% for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0%.
  • gnomAD v4.1: AF=0%.
  • gnomAD-Canada: AF=0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 Variant is absent from population databases; cannot confirm observation in healthy adults. No case-level data showing co-occurrence with another pathogenic variant or presence in an unaffected individual was identified. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • no observation in healthy adult controls.
Still missing
  • No data on presence/absence in healthy individuals.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating no deleterious effect were identified. OncoKB reports Unknown Oncogenic Effect. No publications with experimental data showing benign functional impact for this variant were found. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional data showing no impact.
Still missing
  • No functional studies of p.Pro298Ser available.
Sources
oncokb ↗
BS4 No segregation data available. No family studies showing lack of segregation with disease were identified. Details ▾Hide ▴
Evidence considered
  • No segregation or family data in case materials.
Still missing
  • No family studies or segregation data available.
BP1 GNA11 has established gain-of-function missense mutations (e.g., Q209, R183) causing constitutive activation in somatic disease and missense variants associated with germline vascular malformations. It cannot be concluded that only truncating variants cause GNA11-related disease; missense variants are a recognized disease mechanism. Details ▾Hide ▴
Evidence considered
  • GNA11 disease mechanism includes gain-of-function missense variants (Q209L/P in uveal melanoma) and germline missense variants in vascular malformations. Truncation-only paradigm does not apply.
Sources
pvs1_gene_context
BP2 No data on trans configuration with a known pathogenic variant. No case-level genotyping data was available to assess allelic phase. Details ▾Hide ▴
Evidence considered
  • No trans-phase data available.
Still missing
  • No case-level genotyping or phase data.
BP4 In silico evidence is conflicting: REVEL 0.535 is borderline damaging (>0.5 threshold), while BayesDel -0.247 is confidently benign (<0). Multiple lines of computational evidence do not consistently suggest no impact on the gene product, so BP4 is not met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.535 (borderline damaging).
  • BayesDel: -0.247 (benign).
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP5 No alternate molecular basis identified. No case-level data showing a different causal variant in the proband was available. Details ▾Hide ▴
Evidence considered
  • No alternate causal variant data available.
Still missing
  • No case-level variant data to exclude other molecular causes.
BP6 Absent from ClinVar. No 3-star expert panel or other reputable source has classified NM_002067.5:c.892C>T as benign. BP6 default supporting benign strength cannot be applied without a ClinVar entry. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable source classification available.
Still missing
  • No ClinVar entry exists for this variant.
Sources
clinvar ↗
PS5 No alternate source has classified this variant as pathogenic. The variant is absent from ClinVar and no diagnostic laboratory classification was found. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no reputable source classification available.
Still missing
  • No established pathogenic classification from any source.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 HCI prior data not available for GNA11 (gene not supported by the predictor). Missense constraint (z-score) cannot be assessed without this metric. Gene-level missense tolerance data is unavailable in the case materials. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene_not_supported. No missense constraint score available.
Still missing
  • GNA11 missense constraint/z-score data not available
  • requires external lookup (e.g.
  • gnomAD missense o/e).
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Pro298Ser); does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • PVS1 is reserved for null variants where loss of function is a known disease mechanism.
Sources
pvs1_generic_framework ↗
PM5 N/ANo same-residue pathogenic comparator variant identified. PM5 candidate harvesting returned no candidates at Pro298 with an established pathogenic classification. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates
  • 0 expert-panel P/LP candidates.
Sources
pm5_candidates
BP7 N/AMissense variant; BP7 is reserved for synonymous variants with no predicted splicing impact. NM_002067.5:c.892C>T is a missense substitution (p.Pro298Ser). Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Identifiers

Gene
GNA11
Transcript
NM_002067.5
Coding (HGVS c.)
NM_002067.5:c.892C>T
Protein (HGVS p.)
NP_002058.2:p.(Pro298Ser)
GRCh38
chr19:3120991 C>T
GRCh37
chr19:3120989 C>T
COSMIC
COSV50138421

Gene diagram

Every interpreted variant in GNA11, mapped onto the exon structure of NM_002067.5. Select a row to find it on the plot.

GNA11NM_002067.5
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 +6 bp
0.000
SpliceAI donor lossat -234 bp
0.000
SpliceAI donor gainat -252 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.535
BayesDel
-0.247

How the predictions were used

PP3 In silico predictors are conflicting: REVEL 0.535 (borderline damaging, just above 0.5 threshold), BayesDel -0.247 (benign), SpliceAI max delta 0.00 (no splicing impact). Multiple lines of computational evidence do not consistently support a deleterious effect; the conflicting data does not satisfy PP3 requirements. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.535 (borderline).
  • BayesDel: -0.247 (benign).
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP4 In silico evidence is conflicting: REVEL 0.535 is borderline damaging (>0.5 threshold), while BayesDel -0.247 is confidently benign (<0). Multiple lines of computational evidence do not consistently suggest no impact on the gene product, so BP4 is not met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.535 (borderline damaging).
  • BayesDel: -0.247 (benign).
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AMissense variant; BP7 is reserved for synonymous variants with no predicted splicing impact. NM_002067.5:c.892C>T is a missense substitution (p.Pro298Ser). Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.535. BayesDel score = -0.246968.

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 0.000 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 = 0.00). REVEL score = 0.535. BayesDel score = -0.246968.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GNA11, a G protein subunit, is recurrently mutated in uveal melanoma.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50138421, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.