LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-22
Case ID: NM_002067.5_c.605_2_606del_20260722_110039
Framework: ACMG/AMP 2015
Variant classification summary

NM_002067.5:c.605+2_606del

GNA11  · NP_002058.2:p.?  · NM_002067.5
GRCh37: chr19:3115069 CGGTACCGCCCGGGCCACAGCAGGCGGGGAGGGGGCACTGAGAGGCTCATTTGCCCGGTGTGCCGGCTCATGCCTGCGCACCCAGTGCTTTGGGAGGCCAAGGCGGGAGGATCGCCTGAGTCCAGGAGTTTGAGACCACCCTGGGCAACATAGCCAGACCTCATATCTAAAAAAAATTTTAAAAATTAGCTGGGCGTGGTTGTGTGCACCTGTGGTCCCAGCTACTCAGGAGGCTGAGGCAGGAGGATCGCTCAAGCCCAGGAGGTTGAGGCTGAAGTGAGCCATGATGGCACCACTGGACTCCAGCCTGGGCGACAGAGGGAGACCCTGTTTCGTCTTATTAAACAAAAGAAAGCCCATTGGTCTTCATCCTCAGTGTGTGTTTGACCAGGTCAGGGGATAAGATTTATCTCTAAGTATGTGTGAGCCAGGGCCACACAGGGAAGGAGCTGTGGGGGTGTGGGGGGCGTGGCCACATCCATCCAGACCGGCAGCCGAAGAGACCTGGCAGGGAGGACATTTGACAGGGCCTCCAGGACGGGCCGGGGGCCTGGTTGGAGCCAGCATGGGGCTGGGGTCTGGAGTGCTGGCCGGAGCAGGGGGTGCCGCATGGTGCGGGAGGGGTCATAGGGACTGAGGCTGCCAGGGGAGGGGGCTCATGGGGACCGAGGCTGTGAGGGGAGGAGGGGTCATAGGGACCGAGGCTGTGAGGGGAGGGGGGGGGTCACGGGGACCGAGGCTGTGAGTGGAGGAGGGGTCATAGGGACTGAGTGGGGAGGAGGGGTCATAGGGACTGAGGCTGTGAGGGGAGGAGGGGTCATAGGGGCCGAGGCTGTCAGGGAAGAGGGGTCATGGGGACCGAGGCTGTGAGGGGAGGAGGGGTCGTGGGGACCGAGGCTTTGAGGGGAGGAGGGGTCATAGGGACTGAGTGGGGAGGAGGGCTCCAGGCTGGGGTGGAGGAGCTGGGTGGTGTGGGGTGGATTCTGTTCTTCACGGGCTGCCCCTGCGGATCCTGCTGGGCCTCCGGGGCTCCAGGTCCACTGTGGCTGGGGGCCGGCCAGCAGAGCCGGGTTCTCCCTGGGGACCCTCAGTGGGTCCTGTGTCTGGTAGGCTGCTCAGCTGGCTGGACTCTGCTGTCCCTGGGAACGTGGACCCTGCCTGCCTGTCTCCTGGCCCCATATAACATCTCCAGCGCTGAGGTCCCGGCTTTATGCGTGCCTGTCCTGGGCTGCTGGTGTCGGGCGTGAGACTCCCACCGCAGGCCTTATTCCCGCCCAGTGCTGGAGGCCAGAAGGCTGAGATGCAGGTGTGGGCCGGGCCAGGTCCTTCTGAGGCTGAGGGGATCTGCCCAGGCCTCACTCGGCTCCTAGTGGCGGCCGCATCCTTGGCATCCTTGGCATCCTTGGCATCCTTGGCTTGTGGCCGGGTTGCCTCATCCCTGCCCCCATCCTCATGCAGCGTCCTCCCCGCCTGCGCCTTTGCCTCTGTTCTCTTATAACCTGTCCTTGGCCAGGGCCACCCTACCTCTGTGTGACGTTATCCTAACCAGTGACATCCGCACAGACCCTGTTTCCAGATCAGAGCCGTCCCCGGGTTCTGGTGTTCGTGCGTGTGGGGCGCTAGACGGCTCTGTCCTGGAGGGCCTCGCGGTGGCTCCGGTTGCGGGTGCCTTCTCCTGCAGTGCAAGCTCGCCCTGGCACTGGCCCTCATGAGGGAATGACGCCTCCCTGCCAGGGTGTCCCCACCCAGCTGGTGCACTGCCGAGGCCATTGTGAGGGTTCCGGGAAGTCTGTGGGGTTTTCCTCGAGAGCCCTGCCTTGAGACCCACCCCAGGGCTGGGGGTGCCACCCCCTGCCATCTGCCTGTTCTCCCCACCCGTCCTCCCAGCTCGGCCTCCCAGCGCAGGCAGGGAGGATGCGGCGTGAAGATGGAGGCAGGGATGGAGCAATGTGGCCACAAGCCAAGGAATGCCAAGCTCTGGGATGGTTCCCGGGGACCCGAGCAGGCGCTGGGCCCTCAGAAGCTGCGGTGTCCTCTCTGGACATGGGCGATGGTGTATATTGTTACGAGAATTCAAGTTTTTCTTCTTTTTTATTCACACGGGGCCCATGACCCCAGGATACAGCTGAGGCGAGCCAGGCATAGGCCAGGTTGTGGCATGAATGTCCCCTCACAGCCCCACGCTGGCCTCTTAACAGCGCAGGCCTCTGTGTCCTCTGTCAGAAATGTCCTGTCCCCTCCCTGAGCTGAGCTCAGGCTGGGTGTGTCACCCCCTCTCCACCATCTTCCAGGCCCTTCCCAGCTCCAGCTGTGCCCTTTTCTTTTTTTTGAGACGGAGTCTTGCTCTGTCGCCCAGGCTGGAGTGCAGCTGTGCAATCTGGGCTCACTGCAAGCTCCGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTATAGACGCCCGCCACCACGCCTGGCTAATTTTTTGTACTTTTTAGTAGAGATGTGGTTTCACCATGTTAGCCAGGATGGTCTCGACCTCCTGACCTCGTGATCCGCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCCGGCTGTGCCCTCTGTGCCGGGTGCAGACCCCCGTCCTGAGCCTACTCCTCTGCCACCATTGTTTCTCTGCCAGCCGCCTCTGTCCACCACACGCTGGCAGAGGGCCGGCCAGGTGCTGTGGGATGCAGCTGGAGGCCTTGAAGGCCGGTGGGATCGTCCCAGTGCGTGAGGAGAGGCTCCTGCTCCCTCAGGTGGGGACAAGACACGGGGGGACCCGGATCCCAGCCCTGCCGGCCGCCGCAGGCGTGCAGGAGAGGCCTCGCGCTCCAGACGGGCTGTGGCCTGGTGTCGGCACACCCACTGTCCTCCCGCCTGGCCACAGCTGCTGGTGCGGGCCCTCTTGTCCCTTAGAGTCACCTGGCACATCTGTCATCCACCGGTGCCTGCTGGACTCCCCCGCAGACCAGACCAGGTGGATTTCACCACTCACATGCCCAAAGCAGCCCCGCTCTCCTCGGCAGAGTTGCAGGGACCCCGGCCTTCCCTGGGGCCTGGGGCCAGGGCCTGAGGGGCACTCTCCGCTTCTGCCTTTGTATTCTTTCAAGGAGACCAAAGTGCCTTTTCTCGTTATAGAAAACTTAGAAAAGTCACAAGTAGAAAGAGGCAAACGTCCCGTAAGGAACGCACGCCCGCAGACATCGTCTGAGCTGATTTTCTTTCTCCCGCCTGTGCGTGGCCTGAGAGTGTGAGGTTGAGCTGCTCACCACGCGGGGCAGGGCGCTGCGCCTGCTCTTCTGCCCCAGGAGGATACCGGCAACTCTGCCCTCTGCAGCCGTCACTGGAGGGTCCCTGCAGGGAGCAACTGTGGCATCAGTGTTTACTCCTGCGAGTGACGCTTGGTGAACATCTGTGTCCCTGGCCCAGTGAGGGGAAAGGCTTCTGTGCTCAGGGTGACATCCAGATGCCAGATGTAGGGTCCCTGGGCACCCATCGCAGGTTCCCGCAGCAGCTGGCGCCCAGAATCCTCTGGGTTCTCACACCCCCACACTAGCGCCCGCTTCCCTGGGCCCAGTGGTCTCAGGCCCCTTTGCCAGTGAGGGAAGGGTCTGCGGTGGTCACCCCTGGAGGCGGTGCGGCCGCTCTCTGAGAGCGTCCTTGCCCGTTCTAAGAGTGGGGGCTCTTCCTGCTCCAGCCGATGTCAGTCTGGTGTGGCAGGAGGGGCTTGGGTGGGAGCCGTCCTGGGATTGCAGATTGGGCCTTGGGGCGCCAGGTGGCTGAGTCCTGGCGCTGTGTCCTTTCA>C  ·  GRCh38: chr19:3115071 CGGTACCGCCCGGGCCACAGCAGGCGGGGAGGGGGCACTGAGAGGCTCATTTGCCCGGTGTGCCGGCTCATGCCTGCGCACCCAGTGCTTTGGGAGGCCAAGGCGGGAGGATCGCCTGAGTCCAGGAGTTTGAGACCACCCTGGGCAACATAGCCAGACCTCATATCTAAAAAAAATTTTAAAAATTAGCTGGGCGTGGTTGTGTGCACCTGTGGTCCCAGCTACTCAGGAGGCTGAGGCAGGAGGATCGCTCAAGCCCAGGAGGTTGAGGCTGAAGTGAGCCATGATGGCACCACTGGACTCCAGCCTGGGCGACAGAGGGAGACCCTGTTTCGTCTTATTAAACAAAAGAAAGCCCATTGGTCTTCATCCTCAGTGTGTGTTTGACCAGGTCAGGGGATAAGATTTATCTCTAAGTATGTGTGAGCCAGGGCCACACAGGGAAGGAGCTGTGGGGGTGTGGGGGGCGTGGCCACATCCATCCAGACCGGCAGCCGAAGAGACCTGGCAGGGAGGACATTTGACAGGGCCTCCAGGACGGGCCGGGGGCCTGGTTGGAGCCAGCATGGGGCTGGGGTCTGGAGTGCTGGCCGGAGCAGGGGGTGCCGCATGGTGCGGGAGGGGTCATAGGGACTGAGGCTGCCAGGGGAGGGGGCTCATGGGGACCGAGGCTGTGAGGGGAGGAGGGGTCATAGGGACCGAGGCTGTGAGGGGAGGGGGGGGGTCACGGGGACCGAGGCTGTGAGTGGAGGAGGGGTCATAGGGACTGAGTGGGGAGGAGGGGTCATAGGGACTGAGGCTGTGAGGGGAGGAGGGGTCATAGGGGCCGAGGCTGTCAGGGAAGAGGGGTCATGGGGACCGAGGCTGTGAGGGGAGGAGGGGTCGTGGGGACCGAGGCTTTGAGGGGAGGAGGGGTCATAGGGACTGAGTGGGGAGGAGGGCTCCAGGCTGGGGTGGAGGAGCTGGGTGGTGTGGGGTGGATTCTGTTCTTCACGGGCTGCCCCTGCGGATCCTGCTGGGCCTCCGGGGCTCCAGGTCCACTGTGGCTGGGGGCCGGCCAGCAGAGCCGGGTTCTCCCTGGGGACCCTCAGTGGGTCCTGTGTCTGGTAGGCTGCTCAGCTGGCTGGACTCTGCTGTCCCTGGGAACGTGGACCCTGCCTGCCTGTCTCCTGGCCCCATATAACATCTCCAGCGCTGAGGTCCCGGCTTTATGCGTGCCTGTCCTGGGCTGCTGGTGTCGGGCGTGAGACTCCCACCGCAGGCCTTATTCCCGCCCAGTGCTGGAGGCCAGAAGGCTGAGATGCAGGTGTGGGCCGGGCCAGGTCCTTCTGAGGCTGAGGGGATCTGCCCAGGCCTCACTCGGCTCCTAGTGGCGGCCGCATCCTTGGCATCCTTGGCATCCTTGGCATCCTTGGCTTGTGGCCGGGTTGCCTCATCCCTGCCCCCATCCTCATGCAGCGTCCTCCCCGCCTGCGCCTTTGCCTCTGTTCTCTTATAACCTGTCCTTGGCCAGGGCCACCCTACCTCTGTGTGACGTTATCCTAACCAGTGACATCCGCACAGACCCTGTTTCCAGATCAGAGCCGTCCCCGGGTTCTGGTGTTCGTGCGTGTGGGGCGCTAGACGGCTCTGTCCTGGAGGGCCTCGCGGTGGCTCCGGTTGCGGGTGCCTTCTCCTGCAGTGCAAGCTCGCCCTGGCACTGGCCCTCATGAGGGAATGACGCCTCCCTGCCAGGGTGTCCCCACCCAGCTGGTGCACTGCCGAGGCCATTGTGAGGGTTCCGGGAAGTCTGTGGGGTTTTCCTCGAGAGCCCTGCCTTGAGACCCACCCCAGGGCTGGGGGTGCCACCCCCTGCCATCTGCCTGTTCTCCCCACCCGTCCTCCCAGCTCGGCCTCCCAGCGCAGGCAGGGAGGATGCGGCGTGAAGATGGAGGCAGGGATGGAGCAATGTGGCCACAAGCCAAGGAATGCCAAGCTCTGGGATGGTTCCCGGGGACCCGAGCAGGCGCTGGGCCCTCAGAAGCTGCGGTGTCCTCTCTGGACATGGGCGATGGTGTATATTGTTACGAGAATTCAAGTTTTTCTTCTTTTTTATTCACACGGGGCCCATGACCCCAGGATACAGCTGAGGCGAGCCAGGCATAGGCCAGGTTGTGGCATGAATGTCCCCTCACAGCCCCACGCTGGCCTCTTAACAGCGCAGGCCTCTGTGTCCTCTGTCAGAAATGTCCTGTCCCCTCCCTGAGCTGAGCTCAGGCTGGGTGTGTCACCCCCTCTCCACCATCTTCCAGGCCCTTCCCAGCTCCAGCTGTGCCCTTTTCTTTTTTTTGAGACGGAGTCTTGCTCTGTCGCCCAGGCTGGAGTGCAGCTGTGCAATCTGGGCTCACTGCAAGCTCCGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTATAGACGCCCGCCACCACGCCTGGCTAATTTTTTGTACTTTTTAGTAGAGATGTGGTTTCACCATGTTAGCCAGGATGGTCTCGACCTCCTGACCTCGTGATCCGCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCCGGCTGTGCCCTCTGTGCCGGGTGCAGACCCCCGTCCTGAGCCTACTCCTCTGCCACCATTGTTTCTCTGCCAGCCGCCTCTGTCCACCACACGCTGGCAGAGGGCCGGCCAGGTGCTGTGGGATGCAGCTGGAGGCCTTGAAGGCCGGTGGGATCGTCCCAGTGCGTGAGGAGAGGCTCCTGCTCCCTCAGGTGGGGACAAGACACGGGGGGACCCGGATCCCAGCCCTGCCGGCCGCCGCAGGCGTGCAGGAGAGGCCTCGCGCTCCAGACGGGCTGTGGCCTGGTGTCGGCACACCCACTGTCCTCCCGCCTGGCCACAGCTGCTGGTGCGGGCCCTCTTGTCCCTTAGAGTCACCTGGCACATCTGTCATCCACCGGTGCCTGCTGGACTCCCCCGCAGACCAGACCAGGTGGATTTCACCACTCACATGCCCAAAGCAGCCCCGCTCTCCTCGGCAGAGTTGCAGGGACCCCGGCCTTCCCTGGGGCCTGGGGCCAGGGCCTGAGGGGCACTCTCCGCTTCTGCCTTTGTATTCTTTCAAGGAGACCAAAGTGCCTTTTCTCGTTATAGAAAACTTAGAAAAGTCACAAGTAGAAAGAGGCAAACGTCCCGTAAGGAACGCACGCCCGCAGACATCGTCTGAGCTGATTTTCTTTCTCCCGCCTGTGCGTGGCCTGAGAGTGTGAGGTTGAGCTGCTCACCACGCGGGGCAGGGCGCTGCGCCTGCTCTTCTGCCCCAGGAGGATACCGGCAACTCTGCCCTCTGCAGCCGTCACTGGAGGGTCCCTGCAGGGAGCAACTGTGGCATCAGTGTTTACTCCTGCGAGTGACGCTTGGTGAACATCTGTGTCCCTGGCCCAGTGAGGGGAAAGGCTTCTGTGCTCAGGGTGACATCCAGATGCCAGATGTAGGGTCCCTGGGCACCCATCGCAGGTTCCCGCAGCAGCTGGCGCCCAGAATCCTCTGGGTTCTCACACCCCCACACTAGCGCCCGCTTCCCTGGGCCCAGTGGTCTCAGGCCCCTTTGCCAGTGAGGGAAGGGTCTGCGGTGGTCACCCCTGGAGGCGGTGCGGCCGCTCTCTGAGAGCGTCCTTGCCCGTTCTAAGAGTGGGGGCTCTTCCTGCTCCAGCCGATGTCAGTCTGGTGTGGCAGGAGGGGCTTGGGTGGGAGCCGTCCTGGGATTGCAGATTGGGCCTTGGGGCGCCAGGTGGCTGAGTCCTGGCGCTGTGTCCTTTCA>C
Gene: GNA11 Transcript: NM_002067.5
Final call
Likely Pathogenic
PVS1 very strong PM2 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
GNA11
Transcript
NM_002067.5
Protein
NP_002058.2:p.?
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
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).
3
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.
4
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.
5
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.
Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.
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 Met 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.
pvs1_generic_framework gnomad_v2 gnomad_v4 gnomad_canada
PS1 N/A PS1 applies when a variant has the same amino acid change as a known pathogenic missense variant. This variant is a canonical splice site deletion and does not produce a defined amino acid substitution.
PS2 Not assessed No de novo data are available for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed.
PS3 Not met No functional data are available for this variant. The variant is absent from COSMIC, has no SpliceAI scores, and no literature reports were identified that directly test the functional impact of NM_002067.5:c.605+2_606del.
PS4 Not assessed No case-control or disease prevalence data are available for this variant.
PS5 N/A PS5 applies to variants found in trans with a pathogenic variant in recessive disorders. GNA11-associated disorders follow dominant inheritance; this criterion is not applicable.
PM1 Not met 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. The variant is absent from cancerhotspots.org, and no gene-specific PM1 domain has been defined for GNA11 under generic ACMG.
PM2 Met 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.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 N/A Trivially not applicable per instructions — skipped.
PM4 N/A PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This is a canonical splice site deletion whose protein consequence cannot be determined (p.?) and does not fall into the defined in-frame protein-altering categories for PM4.
PM5 N/A PM5 requires a same-residue missense comparator. This variant is a canonical splice site deletion that cannot be resolved to a defined amino acid residue. Classic same-residue PM5 semantics cannot be confirmed.
PM6 Not assessed No de novo data are available for this variant. PM6 requires confirmed de novo observation.
PP1 Not assessed No co-segregation data are available for this variant.
PP2 N/A PP2 applies to genes where missense variants are a predominant disease mechanism and benign missense variation is rare. This is a canonical splice site deletion, not a missense variant.
PP3 N/A In silico prediction tools (REVEL, BayesDel, HCI prior) are not applicable to this variant type (not SNV). SpliceAI delta scores are unavailable. Furthermore, PP3 should not be double-counted for the same splice-effect evidence already captured by PVS1 under PMC6185798.
PP4 Not assessed No proband phenotype or clinical data are available for this variant.
PP5 Not met This variant is absent from ClinVar. No reputable source has reported this variant as pathogenic.
BA1 Not met This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases. The allele frequency is 0%, well below the BA1 threshold of >1%.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3%.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not assessed No data on observation of this variant in healthy adult individuals are available.
BS3 Not met No well-established functional studies exist showing no deleterious effect for this variant. No functional data of any kind were identified.
BS4 Not assessed No co-segregation data are available to evaluate lack of segregation with disease.
BP1 N/A BP1 applies to missense variants in genes where only truncating variants cause disease. This is a canonical splice site deletion, not a missense variant.
BP2 Not assessed No data are available on observation of this variant in trans with a known pathogenic variant in a recessive disorder.
BP3 N/A BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a canonical splice site deletion, not a defined in-frame protein alteration.
BP4 N/A In silico prediction tools (REVEL, BayesDel, HCI prior) are not applicable to this variant type. No computational evidence is available to support a benign interpretation.
BP5 Not assessed No data are available on an alternate molecular basis for disease in individuals carrying this variant.
BP6 Not met This variant is absent from ClinVar. No reputable source has reported this variant as benign.
BP7 N/A BP7 applies to synonymous variants with no predicted splice impact. This is a canonical splice site deletion, not a synonymous variant.
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