NM_002067.5:c.605+2_606del is a canonical donor splice site deletion affecting intron 4 of GNA11, a gene for which loss of function is an established germline disease mechanism associated with capillary malformations and vascular anomalies.1 This variant abolishes the splice donor consensus sequence and is predicted to result in aberrant splicing with likely frameshift and nonsense-mediated decay, qualifying for PVS1 at very strong strength under ClinGen SVI PVS1 recommendations (PMC6185798).2 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at moderate strength under generic ACMG/AMP guidelines.3 The variant is absent from ClinVar and has not been reported in the literature; no functional data, de novo observations, or co-segregation data are available. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one very strong criterion (PVS1) plus one moderate criterion (PM2) classifies this variant as Likely Pathogenic.4
GNA11
Final classification
Likely Pathogenic
GNA11 c.605+2_606del · p.?
GNA11
NM_002067.5:c.605+2_606del is a canonical donor splice site deletion affecting intron 4 of GNA11, a gene for which loss of function is an established germline disease mechanism associated with capillary malformations and vascular anomalies.
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, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
GNA11 c.605+2_606del
PVS1 + PM2
→
Likely Pathogenic
4
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 · 2 applied · 16 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
This variant deletes the canonical donor splice site at c.605+2 and extends into exon 5 (c.606), abolishing the intron 4 splice donor consensus. GNA11 loss of function is an established germline disease mechanism associated with capillary malformations and vascular anomalies. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice site variants in genes with established LOF mechanism qualify for PVS1 at very strong strength. The affected exon 5 is biologically relevant and the variant is absent from all population databases.
Canonical donor splice site deletion (c.605+2_606del) abolishes intron 4 splice donor consensusGNA11 loss of function is an established germline disease mechanism supported by literatureAbsent from gnomAD v2.1
✓
PM2
moderate
Pathogenic
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the allele frequency threshold for PM2 (<0.1%) under generic ACMG/AMP guidelines.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No functional data are available for this variant.
PS4
No case-control or disease prevalence data are available for this variant.
PM1
Although GNA11 contains critical functional domains including the GTPase domain, this splice site deletion is not situated within a well-established mutational hotspot as defined by ClinGen or VCEP domain-level criteria.
PM6
No de novo data are available for this variant.
PP1
No co-segregation data are available for this variant.
PP4
No proband phenotype or clinical data are available for this variant.
PP5
This variant is absent from ClinVar.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
BS1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
BS2
No data on observation of this variant in healthy adult individuals are available.
BS3
No well-established functional studies exist showing no deleterious effect for this variant.
BS4
No co-segregation data are available to evaluate lack of segregation with disease.
BP2
No data are available on observation of this variant in trans with a known pathogenic variant in a recessive disorder.
BP5
No data are available on an alternate molecular basis for disease in individuals carrying this variant.
BP6
This variant is absent from ClinVar.
N/A · 10
PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links