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GNAQc.208G>TPathogenic
Print report
Variant interpretation report

GNAQ c.208G>T, p.(Glu70Ter)

NM_002072.4:c.208G>T NP_002063.2:p.(Glu70Ter) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About GNAQ

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

NM_002072.4:c.208G>T is a nonsense variant (p.Glu70Ter) in exon 2 of 7, producing a premature termination codon at amino acid 70 of 359. The truncation removes approximately 81% of the protein including the entire GTPase domain and is predicted to trigger nonsense-mediated decay. Under the ClinGen SVI PVS1 framework (PMC6185798), a null variant in a gene where loss of function is a known germline disease mechanism qualifies for PVS1 at very strong strength when NMD is predicted. GNAQ germline loss of function is supported by the literature as a disease mechanism, though the evidence base draws predominantly from somatic and mosaic disease contexts.

PM1Moderate
PM1 · moderate

The variant introduces a premature stop codon (p.Glu70Ter) within the Ras-like GTPase domain of GNAQ (residues 36-355), which is the critical functional domain responsible for GTP binding and hydrolysis. Truncation at codon 70 removes the entire GTPase domain and all downstream functional elements. Under generic ACMG/AMP, PM1 applies when a variant is located in a well-characterized critical functional domain without benign variation. The cancerhotspots.org database does not flag residue 70 as a statistically significant hotspot, but PM1 may be satisfied by domain-level characterization without requiring residue-level hotspot significance.

PM2Moderate
PM2 · moderate

NM_002072.4:c.208G>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), representing a large, diverse population cohort. Under generic ACMG/AMP, absence from population databases at an allele frequency below 0.1% supports a moderate level of evidence for pathogenicity (PM2).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM1 moderate, PM2 moderate; combination = 1 very strong + 2 moderate, which maps to Pathogenic.

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
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. 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 identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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: 3 met · 18 not met · 0 not assessed · 5 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_002072.4:c.208G>T (p.Glu70Ter) is a nonsense variant in exon 2 of GNAQ, introducing a premature termination codon predicted to trigger nonsense-mediated decay and truncating the protein before the GTPase domain. This qualifies as a null variant (PVS1, very strong) under the ClinGen SVI framework (PMC6185798).

The variant is located within the Ras-like GTPase domain (residues 36-355), a critical functional domain for GNAQ GTP-binding and signaling activity. Truncation at codon 70 eliminates the entire GTPase domain (PM1, moderate).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, representing a large, diverse population cohort with allele frequency 0.0% (PM2, moderate).

Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), one very strong criterion (PVS1) plus two moderate criteria (PM1, PM2) meets the threshold for Pathogenic classification.

Caution is warranted: GNAQ germline loss-of-function disease mechanism is not established by an official ClinGen CSPEC/VCEP. The supporting literature is drawn predominantly from somatic cancer and mosaic cutaneous disorder contexts. A definitive germline tumor predisposition syndrome from GNAQ LoF has not been independently validated.

Met · 3

PVS1 Very strongNM_002072.4:c.208G>T is a nonsense variant (p.Glu70Ter) in exon 2 of 7, producing a premature termination codon at amino acid 70 of 359. The truncation removes approximately 81% of the protein including the entire GTPase domain and is predicted to trigger nonsense-mediated decay. Under the ClinGen SVI PVS1 framework (PMC6185798), a null variant in a gene where loss of function is a known germline disease mechanism qualifies for PVS1 at very strong strength when NMD is predicted. GNAQ germline loss of function is supported by the literature as a disease mechanism, though the evidence base draws predominantly from somatic and mosaic disease contexts. Details ▾Hide ▴
Evidence considered
  • Nonsense variant c.208G>T introduces premature stop at codon 70 (p.Glu70Ter)
  • Variant located in exon 2 of 7
  • early truncation predicted to trigger NMD
  • Truncation removes >80% of protein including the entire Ras-like GTPase domain (residues 36-355)
  • GNAQ germline loss-of-function mechanism supported by literature (pvs1_gene_gate: eligible)
  • Absent from gnomAD v2.1 and v4.1
  • consistent with a disease-causing null variant
  • Generic PVS1 framework from PMC6185798 applied
  • no gene-specific CSPEC/VCEP PVS1 rules available
Still missing
  • GNAQ germline LoF disease mechanism is not supported by an official ClinGen CSPEC/VCEP
  • supporting literature is predominantly somatic/mosaic context
  • PMD:39344744 explicitly states GNAQ lacked pathogenic germline variants in a Finnish uveal melanoma cohort
  • germline tumor predisposition from GNAQ LoF remains uncertain
  • No patient phenotype data available to confirm relevance of this specific variant to a germline disorder
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentgnomad_v2 ↗gnomad_v4 ↗
PM1 ModerateThe variant introduces a premature stop codon (p.Glu70Ter) within the Ras-like GTPase domain of GNAQ (residues 36-355), which is the critical functional domain responsible for GTP binding and hydrolysis. Truncation at codon 70 removes the entire GTPase domain and all downstream functional elements. Under generic ACMG/AMP, PM1 applies when a variant is located in a well-characterized critical functional domain without benign variation. The cancerhotspots.org database does not flag residue 70 as a statistically significant hotspot, but PM1 may be satisfied by domain-level characterization without requiring residue-level hotspot significance. Details ▾Hide ▴
Evidence considered
  • Premature stop at codon 70 located within the Ras-like GTPase domain (residues ~36-355)
  • a well-characterized critical functional domain
  • Truncation removes the entire GTPase domain and all downstream functional elements (G1-G5 boxes
  • switch regions)
  • Domain-level application under generic ACMG: cancerhotspots.org does not flag residue 70 as a statistically significant hotspot
  • but a well-characterized functional domain may satisfy PM1 without residue-level hotspot statistics
Still missing
  • Residue 70 is not a cancerhotspots.org significant hotspot
  • PM1 is applied on domain characterization rather than residue-level hotspot statistics
  • No GNAQ-specific domain criteria from a CSPEC/VCEP
  • generic ACMG domain-level application used
PM2 ModerateNM_002072.4:c.208G>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), representing a large, diverse population cohort. Under generic ACMG/AMP, absence from population databases at an allele frequency below 0.1% supports a moderate level of evidence for pathogenicity (PM2). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
  • Allele frequency = 0.0% across all queried population databases
  • well below PM2 threshold of <0.1%
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 18 · evaluated, threshold not reached

PS1 PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change, with the comparator variant previously established as pathogenic. NM_002072.4:c.208G>T produces a premature stop codon (p.Glu70Ter). No alternative nucleotide change at codon 70 producing the same nonsense change with an established pathogenic classification has been identified. Details ▾Hide ▴
Still missing
  • No alternative nucleotide substitution at codon 70 producing a stop codon with established pathogenicity was identified in ClinVar or literature
PS2 PS2 requires a de novo occurrence with both maternity and paternity confirmed. No de novo data are available for NM_002072.4:c.208G>T. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 PS3 requires variant-specific functional evidence from published experimental studies. No functional studies testing NM_002072.4:c.208G>T (p.Glu70Ter) were identified in the evidence brief, literature pass, or any reviewed publications. The OncoKB classification is 'Unknown Oncogenic Effect' and does not provide functional data for this variant. Details ▾Hide ▴
Still missing
  • No experimental functional studies identified for this variant
PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals versus controls. No case-control data or prevalence studies are available for NM_002072.4:c.208G>T. Details ▾Hide ▴
Still missing
  • No case-control or enrichment data available
PM5 PM5 requires a different missense change at the same amino acid residue that has been established as pathogenic. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a missense change. The pm5_candidates harvest found zero comparator variants at residue 70 in ClinVar. The well-characterized GNAQ pathogenic missense hotspots (Q209, R183) are at different residues and do not satisfy the same-codon requirement for PM5. Details ▾Hide ▴
Evidence considered
  • Variant is a nonsense
  • not a missense change
  • pm5_candidates reported zero same-residue comparator variants in ClinVar
  • Known GNAQ pathogenic missense residues (Q209
  • R183) are at different codons
  • PM5 recommendation: not_applicable per artifact
  • confirmed on manual review
Sources
pm5_candidates
PM6 PM6 requires a de novo occurrence without confirmation of maternity and paternity. No de novo data are available for NM_002072.4:c.208G>T. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data are available for NM_002072.4:c.208G>T. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient phenotype or family history data are available for this case. Details ▾Hide ▴
Still missing
  • No patient phenotype or family history data available
PP5 PP5 requires a reputable source to have recently reported the variant as pathogenic. NM_002072.4:c.208G>T is absent from ClinVar with no submissions from any submitter. No expert panel or clinical laboratory has classified this variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • zero submissions
  • zero classifications
Sources
clinvar ↗
BA1 BA1 requires an allele frequency >5% in any general population database. NM_002072.4:c.208G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada with an allele frequency of 0.0%. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0% in gnomAD v2.1
  • v4.1
  • and gnomAD-Canada
  • Far below BA1 threshold of >5%
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires an allele frequency greater than expected for the disorder (threshold >0.3% under non-VCEP generic ACMG). NM_002072.4:c.208G>T is absent from all queried population databases (allele frequency 0.0%). Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0% across all population databases
  • Far below BS1 threshold of >0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age. No data indicating observation of NM_002072.4:c.208G>T in healthy adults are available. The variant is absent from all population databases. Details ▾Hide ▴
Still missing
  • No observation of variant in healthy controls documented
BS3 BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No functional studies testing NM_002072.4:c.208G>T were identified. Details ▾Hide ▴
Still missing
  • No functional studies identified
BS4 BS4 requires lack of segregation with disease in affected family members. No segregation data are available for NM_002072.4:c.208G>T. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 BP2 requires observation of the variant in trans with a pathogenic dominant variant, or in cis with a known pathogenic variant in a recessive gene. No phase data are available for NM_002072.4:c.208G>T. Details ▾Hide ▴
Still missing
  • No phase or co-occurrence data available
BP5 BP5 requires that the variant be found in a case with an alternate molecular basis for disease. No data indicating an alternate molecular cause in a patient carrying NM_002072.4:c.208G>T are available. Details ▾Hide ▴
Still missing
  • No data on alternate molecular basis in variant carriers
BP6 BP6 requires a reputable source to have reported the variant as benign. NM_002072.4:c.208G>T is absent from ClinVar with no classifications from any submitter. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • zero submissions
Sources
clinvar ↗
PS5 PS5 requires a reputable source to have recently reported the variant as pathogenic but the evidence is not available for independent evaluation. NM_002072.4:c.208G>T is absent from ClinVar and has not been reported as pathogenic by any source. Details ▾Hide ▴
Still missing
  • Variant absent from ClinVar
  • no reputable source classification available
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene product. NM_002072.4:c.208G>T introduces a premature stop codon (p.Glu70Ter), which is inherently deleterious. The deleterious effect of a null variant is already captured by PVS1; applying PP3 to the same null effect would constitute double-counting. BayesDel score (0.588) and SpliceAI max delta (0.04) are noted but not applied under PP3 for a nonsense variant. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.588 (above deleterious threshold) noted but PP3 not applied to avoid double-counting with PVS1
  • SpliceAI max delta 0.04 (no significant splice impact)
BP1 N/ABP1 applies to missense variants in genes where only truncating variants are a known disease mechanism. NM_002072.4:c.208G>T is itself a truncating (nonsense) variant, not a missense change, so BP1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. NM_002072.4:c.208G>T is a nonsense variant introducing a premature stop codon, a clearly damaging molecular consequence. Computational prediction of benign impact is not meaningful for a null variant. SpliceAI predicts no splice impact (max delta 0.04), but this does not negate the damaging effect of the stop-gain itself. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.04 (no splice impact predicted)
  • Nonsense variant
  • stop-gain effect is inherently damaging
  • making benign computational prediction irrelevant
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
GNAQ
Transcript
NM_002072.4
Coding (HGVS c.)
NM_002072.4:c.208G>T
Protein (HGVS p.)
NP_002063.2:p.(Glu70Ter)
GRCh38
chr9:77922274 C>A
GRCh37
chr9:80537190 C>A

Gene diagram

Every interpreted variant in GNAQ, mapped onto the exon structure of NM_002072.4. Select a row to find it on the plot.

GNAQNM_002072.4
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 +71 bp
0.010
SpliceAI acceptor gainat +475 bp
0.000
SpliceAI donor lossat +498 bp
0.040
SpliceAI donor gainat +51 bp
0.000
Pangolin splice lossmagnitude shown
-0.040
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.588

How the predictions were used

PP3 N/APP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene product. NM_002072.4:c.208G>T introduces a premature stop codon (p.Glu70Ter), which is inherently deleterious. The deleterious effect of a null variant is already captured by PVS1; applying PP3 to the same null effect would constitute double-counting. BayesDel score (0.588) and SpliceAI max delta (0.04) are noted but not applied under PP3 for a nonsense variant. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.588 (above deleterious threshold) noted but PP3 not applied to avoid double-counting with PVS1
  • SpliceAI max delta 0.04 (no significant splice impact)
BP4 N/ABP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. NM_002072.4:c.208G>T is a nonsense variant introducing a premature stop codon, a clearly damaging molecular consequence. Computational prediction of benign impact is not meaningful for a null variant. SpliceAI predicts no splice impact (max delta 0.04), but this does not negate the damaging effect of the stop-gain itself. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.04 (no splice impact predicted)
  • Nonsense variant
  • stop-gain effect is inherently damaging
  • making benign computational prediction irrelevant
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002072.4:c.208G>T is a nonsense (stop-gain) variant, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.588046.

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 0.040 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 = 0.04). BayesDel score = 0.588046.

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.