Variant classification summary

NM_002067.5:c.604C>T

GNA11 · NP_002058.2:p.(Arg202Trp) · NM_002067.5

GRCh37: chr19:3115069 C>T · GRCh38: chr19:3115071 C>T

Gene: GNA11 Transcript: NM_002067.5

Final call

VUS

PM1 supporting PM2 supporting PP3 supporting

Variant details

Gene

GNA11

Transcript

NM_002067.5

Protein

NP_002058.2:p.(Arg202Trp)

gnomAD AF

3.100444479720613e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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).

3

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.

4

PP3 (supporting): REVEL predicts a deleterious effect (score 0.774). SpliceAI shows no splicing impact (max delta 0.01). BayesDel is equivocal (0.232).

5

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).

6

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) does not apply to missense variants; variant bucket is 'other' with apply_generic_pvs1_framework set to false.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No known pathogenic variant at codon 202 exists in ClinVar or the literature to serve as a comparator. The variant is entirely absent from ClinVar, and no different nucleotide change producing the same p.Arg202Trp amino acid change has been reported.	clinvar
PS2	Not met	No de novo data are available for this variant. No publications or clinical reports documenting de novo occurrence were identified.
PS3	Not met	No variant-specific functional studies were identified. The literature search returned zero PMIDs for this variant, and OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. COSMIC reports 3 somatic occurrences, but these are observational, not experimental functional data. No publications testing NM_002067.5:c.604C>T or a systematically characterized range encompassing position 202 were found.	oncokb
PS4	Not met	No case-control or prevalence data are available comparing this variant in affected versus unaffected individuals. The variant is absent from ClinVar, precluding any case-level enrichment analysis.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	This variant is absent from ClinVar; no expert panel or established reputable source has classified it as pathogenic.	clinvar
PM1	Met	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.	oncokb
PM2	Met	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_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variants at the same residue (R202) have been identified in ClinVar. The PM5 candidate search was unable to confirm classic same-residue semantics; no comparator variants at this codon are available for assessment.	pm5_candidates clinvar
PM6	Not met	No de novo data are available for this variant. No publications or clinical reports documenting de novo occurrence with confirmed maternity/paternity were identified.
PP1	Not met	No co-segregation data are available for this variant. No family studies or pedigrees were identified in the literature or databases.
PP2	Not met	Insufficient constraint data are available to assess whether GNA11 has a low rate of benign missense variation. No HCI prior probability, gnomAD missense z-score, or gene-level constraint metrics were available in the evidence files. While GNA11 is a highly conserved G-protein alpha subunit with specific activating missense mutations as the disease mechanism (gain-of-function at R202 and Q228), formal PP2 requires quantitative constraint data that are not present.
PP3	Met	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 bayesdel spliceai
PP4	Not met	No phenotype or family history data are available for this proband. The variant's phenotype specificity cannot be assessed without clinical context.
PP5	Not met	This variant is absent from ClinVar. No expert panel or reputable source classification is available to apply PP5.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 3.10e-6 (0.00031%), which is far below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 3.10e-6 (0.00031%), which is far below the 0.3% threshold for BS1. The highest subpopulation frequency is in European (Finnish) at 3.17e-5 (0.00317%), still well below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of this variant are reported in gnomAD v2.1 or v4.1. The variant is present only in heterozygous state (5/1,612,672 alleles, 0 homozygotes).	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and no variant-specific functional studies were found in the literature.	oncokb
BS4	Not met	No segregation data are available to evaluate lack of segregation with disease.
BP1	N/A	GNA11 disease mechanism is gain-of-function through specific activating missense mutations (e.g., R202, Q228), not loss-of-function through truncating variants. BP1 applies only when truncating variants are the primary disease mechanism, making a missense variant less likely to be pathogenic. This premise does not hold for GNA11.
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant.
BP4	Not met	REVEL score of 0.774 supports a deleterious effect, contradicting the requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.232) is equivocal and SpliceAI (0.01) shows no splicing impact, but REVEL alone is sufficient to prevent BP4 from being met.	revel bayesdel spliceai
BP5	Not met	No data are available regarding an alternative molecular basis for disease in this case.
BP6	Not met	This variant is absent from ClinVar; no benign or likely benign classification from a reputable source is available.	clinvar
BP7	N/A	NM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splicing impact.

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