GNA11

Final classification

VUS

GNA11 c.604C>T · p.Arg202Trp

GNA11

PVS1 is not applicable: NM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a null variant.

Gene

GNA11

Transcript

NM_002067.5

HGVS · transcript:coding

NM_002067.5:c.604C>T

Consequence

N/A

GRCh38

chr19:3115071 C>T

GRCh37

chr19:3115069 C>T

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, PP3 supporting; combination = 3 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, PP3 supporting; combination = 3 supporting, which maps to VUS.

Classification rationale

PM1PM2PP3 VUS

GNA11 c.604C>T

PVS1 is not applicable: NM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a null variant.¹ PM1 (supporting): The variant is located at the catalytic arginine residue R202 in the GTPase switch I region of GNA11, a well-characterized functional domain essential for GTP hydrolysis. This residue is homologous to the canonical hotspot residues GNAQ R183 and GNAS R201. COSMIC confirms 3 somatic occurrences (COSV99030259).² PM2 (supporting): The variant is present in gnomAD v4.1 at an extremely low frequency (5/1,612,672 alleles, AF=3.10e-6, 0 homozygotes), well below the 0.1% threshold. It is absent from gnomAD v2.1 and gnomAD-Canada.³ PP3 (supporting): REVEL predicts a deleterious effect (score 0.774). SpliceAI shows no splicing impact (max delta 0.01). BayesDel is equivocal (0.232).⁴ All other assessed criteria are either not met (PS2, PS3, PS4, PM6, PP1, PP2, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP2, BP4, BP5, BP6) or not applicable (PVS1, PS1, PS5, PM5, BP1, BP7). Combination: PM1 (supporting) + PM2 (supporting) + PP3 (supporting) = 3 supporting criteria. Under ACMG/AMP 2015 rules, 3 supporting criteria do not reach the threshold for Likely Pathogenic (requires ≥4 supporting, or ≥1 moderate + ≥2 supporting, or ≥2 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).⁵

PM1 + PM2 + PP3 → VUS

1 pvs1_variant_assessment

2 oncokb ↗

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 revelbayesdelspliceai ↗

5 generic_acmg_combination_rules

Gene diagram · NM_002067.5 · variants mapped to exon structure

GNA11 NM_002067.5

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM1 supporting Pathogenic

The variant p.Arg202Trp is located in the GTPase domain (switch I region) of GNA11 at the catalytic arginine residue (R202), which is essential for GTP hydrolysis. This is a well-characterized functional domain in G-alpha subunits, homologous to GNAQ R183 and GNAS R201. Mutation at this residue disrupts GTPase activity, leading to constitutive G-protein activation. The variant has been observed in COSMIC (COSV99030259, n=3 somatic occurrences), confirming its relevance in oncogenic contexts. However, cancerhotspots.org does not flag GNA11 R202 as statistically significant at the residue level, limiting strength to supporting.

Located at catalytic arginine R202 in GTPase switch I regionWell-characterized functional domain in G-alpha subunitsCOSMIC COSV99030259: 3 somatic occurrences

oncokb ↗

✓

PM2 supporting Pathogenic

This variant is present in gnomAD v4.1 at an extremely low allele frequency (AF=3.10e-6, 5/1,612,672 alleles, 0 homozygotes), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada. The grpmax filtering allele frequency is 6.8e-7, further supporting rarity. However, because the variant is not completely absent (5 alleles detected), the strength is downgraded from moderate to supporting.

gnomAD v4.1: 5/1612672 alleles

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

REVEL score of 0.774 supports a deleterious effect on protein function. BayesDel score of 0.232 is equivocal and does not independently support or refute pathogenicity. SpliceAI predicts no significant splice impact (max delta 0.01). At least one line of computational evidence (REVEL) supports a deleterious effect, meeting PP3 at supporting level.

REVEL: 0.774 (damaging)BayesDel: 0.232 (equivocal)SpliceAI: max delta 0.01 (no splice impact)

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo data are available for this variant.

PS3 No variant-specific functional studies were identified.

PS4 No case-control or prevalence data are available comparing this variant in affected versus unaffected individuals.

PM6 No de novo data are available for this variant.

PP1 No co-segregation data are available for this variant.

PP2 Insufficient constraint data are available to assess whether GNA11 has a low rate of benign missense variation.

PP4 No phenotype or family history data are available for this proband.

PP5 This variant is absent from ClinVar.

Benign

BA1 The allele frequency in gnomAD v4.1 is 3.10e-6 (0.00031%), which is far below the 1% threshold for BA1.

BS1 The allele frequency in gnomAD v4.1 is 3.10e-6 (0.00031%), which is far below the 0.3% threshold for BS1.

BS2 No homozygous observations of this variant are reported in gnomAD v2.1 or v4.1.

BS3 No well-established functional studies demonstrating no deleterious effect were identified.

BS4 No segregation data are available to evaluate lack of segregation with disease.

BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant.

BP4 REVEL score of 0.774 supports a deleterious effect, contradicting the requirement that multiple lines of computational evidence suggest no impact.

BP5 No data are available regarding an alternative molecular basis for disease in this case.

BP6 This variant is absent from ClinVar; no benign or likely benign classification from a reputable source is available.

N/A · 5 PVS1 · PS1 · PM5 · BP1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.10044e-06; MAF= 0.00031%, 5/1612672 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.16666e-05; MAF= 0.00317%, 2/63158 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,612,672
0 hom · FAF 6.8e-05%

European (Finnish) 2 / 63,158	0.0032%
European (non-Finnish) 3 / 1,179,574	0.00025%

+ 8 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.774. BayesDel score = 0.232155.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99030259, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots