No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYCN is a transcription factor that controls the expression of genes involved in cell growth, division, survival, and metabolism. It is normally active mainly during embryonic development and is largely restricted to cells of the nervous system and a few other tissues. Amplification of MYCN drives cancer, most notably neuroblastoma, and is also seen in medulloblastoma, glioblastoma, and other solid tumors such as breast and small cell lung cancers.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (Moderate): extremely rare in gnomAD v4.1 — 3/1,614,106 alleles (AF 0.00019%), zero homozygotes.
Met (Supporting): REVEL score 0.214 falls at or below the 0.290 BP4-supporting threshold.
VUS: only PM2 (Moderate) and BP4 (Supporting) were met under the generic ACMG/AMP 2015 fallback — insufficient to reach any pathogenic or benign classification.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 3 / 1,614,106 alleles. Recorded AF 1.85861e-06. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.214. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYCN, a transcription factor, is altered by amplification and overexpression in a variety of cancer types including in neuroblastoma.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 16 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No CSPEC/VCEP framework for MYCN was located; generic ACMG/AMP semantics were used as fallback for all codon/residue/domain criteria.
The variant NP_005369.2:p.(Gly309Val) at codon 309 has no ClinVar entry, no cancerhotspots.org or OncoKB hotspot/functional annotation, and no confirmed same-residue comparator variant in the evidence bundle, so PS1, PM1, and PM5 could not be positively assessed and are reported as not_assessed pending human review.
PP2 could not be assessed for lack of gene-level missense constraint statistics, though MYCN's known bifurcated LOF (Feingold syndrome)/GOF missense (Megalencephaly-Polydactyly Syndrome) mechanism was noted as relevant context.
BP1 was deemed not_applicable because MYCN missense variants are an established, non-background disease mechanism (GOF variants causing Megalencephaly-Polydactyly Syndrome), so the BP1 precondition (gene where disease is primarily due to truncating variants and missense is generally benign) is not met.
No VCEP/CSPEC exists for MYCN in this case (generic ACMG fallback in effect).
No functional/biochemical assay literature was retrieved for NM_005378.5:c.926G>T (p.Gly309Val); literature_pass.json returned 0 PMIDs.
OncoKB's only relevant content is non-variant-specific gene-level biology (MYCN amplification/overexpression in neuroblastoma), which cannot support PS3 or BS3 for this specific missense substitution.
Both PS3 and BS3 are returned as not_assessed due to complete absence of applicable functional evidence.
MYCN c.926G>T (p.Gly309Val) is a missense variant with no applicable ClinGen VCEP-specific PP3/BP4 lookup table; generic ClinGen SVI-calibrated REVEL thresholds (Pejaver et al. 2022, PMID 36413997) were applied.
REVEL = 0.214 falls in the BP4-supporting benign range (<=0.290) and does not reach the PP3-supporting pathogenic threshold (>=0.644).
SpliceAI max delta score of 0.01 indicates no predicted splice disruption, consistent with (not additive to) the BP4-supporting call.
BayesDel score was available but withheld from scoring because no verified, citable published calibration threshold exists for it in this pipeline.
This is not a synonymous variant, so BP7 was not assessed.
No criteria match.
PM2 is met at moderate strength under the generic ACMG/AMP fallback. Although not absent, the variant is extremely rare in gnomAD v4.1: 3/1,614,106 alleles (AF 0.000185861%), all in the East Asian subset (3/44,876; AF 0.00668509%), with zero homozygotes and joint grpmax FAF 0.001773%. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. The nonzero v4.1 observations therefore do not preclude PM2 but must not be represented as complete absence from population databases.
Generic ACMG/AMP PM2: absent from controls or present only at an extremely low population frequency; the available population data support extreme rarity but not literal absence.
REVEL score = 0.214 (revel) falls at or below the ClinGen SVI Pejaver et al. 2022 (PMID 36413997) BP4-supporting threshold of REVEL <= 0.290, but is above the BP4-moderate threshold of REVEL <= 0.183, so BP4 is met at supporting strength only. SpliceAI max delta score = 0.01 (spliceai) is essentially null, corroborating a benign computational signal from the splice-impact path but is not stacked as additional strength since it reflects the same overall low-impact prediction rather than an independent calibrated line of evidence. BayesDel score -0.300447 (bayesdel) was not used because no verified, citable published calibration threshold for BayesDel is available to this pipeline.
ClinGen SVI calibrated REVEL thresholds (Pejaver et al. 2022, PMID 36413997), BP4 supporting tier, applied under generic ACMG/AMP framework.
This is a missense variant (NM_005378.5:c.926G>T, p.(Gly309Val)). No gene-specific ClinGen VCEP is available for MYCN (case_summary.framework_mode = generic_acmg; vcep_materials.final_classification_framework.found = false), so generic calibrated computational thresholds apply. REVEL score = 0.214 (revel), well below the ClinGen SVI Pejaver et al. 2022 (PMID 36413997) supporting-pathogenic threshold of REVEL >= 0.644, so PP3 is not supported by the missense in-silico predictor. SpliceAI max delta score = 0.01 (spliceai), far below any splice-impact threshold (~0.1-0.2), so the splice-impact path also does not support PP3. BayesDel score of -0.300447 was returned by the local lookup (bayesdel) but no verified published calibration threshold for BayesDel is available to this pipeline, so it is treated as not_available and was not used to score this criterion.
ClinGen SVI calibrated REVEL thresholds (Pejaver et al. 2022, PMID 36413997) applied under generic ACMG/AMP framework; SpliceAI max delta score below splice-impact threshold.
PP5 is not met because ClinVar has no exact-variant record and therefore no exact-variant pathogenic or likely pathogenic expert-panel assertion.
PP5 is applied only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
BA1 is not met. The highest observed population frequency is 0.00669% in the East Asian gnomAD v4.1 subset (3/44,876 alleles); the joint grpmax FAF is 0.001773%. These values are far below the generic ACMG/AMP stand-alone benign-frequency criterion.
Generic ACMG/AMP BA1: stand-alone benign evidence requires an allele frequency above the stand-alone benign threshold; this variant's highest observed frequency and grpmax FAF do not approach that threshold.
BS1 is not met. The highest observed frequency is 0.00669% in East Asian gnomAD v4.1 (3/44,876 alleles), with joint grpmax FAF 0.001773%; this is not a frequency greater than expected for a rare MYCN-associated dominant developmental disorder.
Generic ACMG/AMP BS1: allele frequency must be greater than expected for the disorder; no disease-calibrated MYCN threshold is available, and the observed frequency is extremely low.
BP6 is not met because ClinVar has no exact-variant record and therefore no exact-variant benign or likely benign expert-panel assertion.
BP6 is applied only to an exact-variant ClinVar expert-panel Benign or Likely benign classification.
PS1 requires a different nucleotide change producing the identical amino acid change (p.Gly309Val) with an established pathogenic classification. This variant (NM_005378.5:c.926G>T, p.(Gly309Val)) is absent from ClinVar, and no other codon change resulting in the same p.Gly309Val substitution was found in the evidence bundle. No governing CSPEC/VCEP framework for MYCN was located, so generic ACMG semantics apply, and there is no comparator to evaluate.
No case-level proband phenotype, parental genotype, parentage confirmation, or inheritance-testing result is provided for NM_005378.5:c.926G>T (p.Gly309Val); de novo occurrence cannot be established.
Generic ACMG/AMP 2015 fallback; PS2 requires a de novo occurrence with the relevant clinical context.
No functional/biochemical assay data (e.g., transcriptional activity, dimerization, transactivation, or cell-based proliferation assays) for MYCN p.(Gly309Val) were identified. No ClinGen VCEP specification exists for MYCN (cspec.found=false, vcep_materials empty), literature_pass.json returned zero PMIDs, and OncoKB explicitly notes no variant-specific reviewed functional evidence, only gene-level context on MYCN amplification/overexpression in neuroblastoma which does not address this missense substitution. Without any validated assay evidence, PS3 cannot be assessed.
No case-control or statistically interpretable case-enrichment evidence for MYCN c.926G>T (p.Gly309Val) was supplied.
Generic ACMG/AMP PS4: prevalence in affected individuals must be significantly increased compared with controls.
PM1 requires the variant to lie in a well-established mutational hotspot or critical, well-characterized functional domain without benign variation. Residue Gly309 of MYCN (NP_005369.2, 464 aa) was queried against cancerhotspots.org and OncoKB and no statistically significant hotspot or variant-specific functional annotation was returned at this position. No CSPEC/VCEP domain map for MYCN was available. The gene-context literature review (embedded in pvs1_gene_context) describes MYCN's known functional hotspots as (a) the C-terminal bHLH-leucine-zipper dimerization/DNA-binding domain (encoded by exons 2-3) and (b) the N-terminal Thr58/Pro60 phosphodegron region where gain-of-function missense variants (e.g., T58M, P60Leu) cause Megalencephaly-Polydactyly Syndrome; residue 309 was not identified as falling within either of these characterized regions in any source consulted. Without an authoritative domain boundary map or hotspot statistic covering residue 309, PM1 cannot be confidently applied or excluded.
Not assessed. No affected-proband observation of MYCN c.926G>T (p.Gly309Val) with a pathogenic/likely pathogenic variant in trans was identified. MYCN-related Feingold syndrome type 1 is described as an autosomal dominant disorder, so the recessive allelic observation required for generic PM3 is not established for this case.
Generic ACMG/AMP PM3: in a recessive disorder, the variant is detected in trans with a pathogenic variant.
PM5 requires a different missense change at the same residue (Gly309) previously established as pathogenic. The pipeline's own PM5 candidate-harvesting step explicitly reported it could not safely confirm classic same-residue PM5 semantics for this variant and returned zero same-residue candidates, instructing that PM5 not be applied from that artifact alone. No other source in the bundle identifies an alternate pathogenic missense change at codon 309.
No report of a de novo occurrence without confirmed parentage is provided for NM_005378.5:c.926G>T (p.Gly309Val).
Generic ACMG/AMP 2015 fallback; PM6 is based on an assumed de novo occurrence when parentage is not confirmed.
No informative affected or unaffected relatives, genotypes, phenotypes, or meioses are reported for NM_005378.5:c.926G>T (p.Gly309Val); cosegregation cannot be evaluated.
Generic ACMG/AMP 2015 fallback; PP1 requires cosegregation of the variant with disease in affected family members.
PP2 requires that missense variants be a common mechanism of disease in the gene and that the gene have a low rate of benign missense variation. MYCN has a dual, residue-dependent mechanism: nonsense/frameshift variants causing loss-of-function/haploinsufficiency are the established cause of Feingold syndrome type 1, while a distinct subset of gain-of-function missense variants clustered at the Thr58/Pro60 phosphodegron cause Megalencephaly-Polydactyly Syndrome. This mixed mechanism means missense pathogenicity in MYCN is highly position-dependent rather than uniformly common across the gene, and no gene-level missense constraint statistic (e.g., missense Z-score, proportion of ClinVar-classified missense variants that are pathogenic) is present anywhere in the evidence bundle to support or refute PP2 at a gene-wide level. No CSPEC/VCEP framework was available to supply a MYCN-specific PP2 rule.
No proband phenotype, diagnostic context, or phenotype-to-MYCN specificity assessment is available for this exact variant.
Generic ACMG/AMP PP4: the patient's phenotype or family history must be highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed. gnomAD v4.1 reports no homozygotes, and the record does not provide phenotype, age, or clinical-status evidence demonstrating occurrence in unaffected adults for a fully penetrant early-onset MYCN-associated disorder.
Generic ACMG/AMP BS2: observation in healthy adults requires disease penetrance and age-of-onset context; allele counts alone are insufficient.
No functional assay data demonstrating normal/wild-type-equivalent activity for MYCN p.(Gly309Val) were identified. Same evidentiary gaps as PS3: no MYCN VCEP specification, zero PMIDs from literature search, and OncoKB provides only non-variant-specific gene-level context. No basis to assess BS3.
No informative non-segregation observations are reported for NM_005378.5:c.926G>T (p.Gly309Val); BS4 cannot be evaluated.
Generic ACMG/AMP 2015 fallback; BS4 requires demonstrated lack of segregation in affected family members.
Not assessed. No observation was identified of MYCN c.926G>T (p.Gly309Val) in cis or trans with a pathogenic/likely pathogenic variant in an affected individual, nor in a healthy individual, that would support generic BP2.
Generic ACMG/AMP BP2: the variant is observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.
No individual-level phenotype or independent molecular diagnosis is supplied to determine whether this variant was observed in a case with an alternative cause of disease.
Generic ACMG/AMP BP5: a variant is found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005378.5:c.926G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Gly309Val). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005378.5:c.926G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Gly309Val). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP1 applies to genes where disease is caused primarily by truncating variants and missense variants are generally benign. MYCN does not meet this precondition: a well-characterized subset of missense variants (gain-of-function changes at the Thr58/Pro60 phosphodegron, e.g., T58M, P60Leu) is an established, distinct pathogenic mechanism causing Megalencephaly-Polydactyly Syndrome, alongside the separate loss-of-function/truncating mechanism for Feingold syndrome type 1. Because missense variation is a recognized disease mechanism in this gene (not merely tolerated background variation), BP1's precondition is not satisfied and the criterion is not applicable to MYCN missense variants generally, including this one.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005378.5:c.926G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Gly309Val). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005378.5:c.926G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Gly309Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in MYCN, mapped onto the exon structure of NM_005378.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| East Asian3 / 44,876 | 6.7e-05 |
This variant is present in gnomAD v4.1 (AF= 1.85861e-06; MAF= 0.00019%, 3/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.68509e-05; MAF= 0.00669%, 3/44876 alleles, homozygotes = 0); grpmax FAF= 1.773e-05.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
REVEL score = 0.214 (revel) falls at or below the ClinGen SVI Pejaver et al. 2022 (PMID 36413997) BP4-supporting threshold of REVEL <= 0.290, but is above the BP4-moderate threshold of REVEL <= 0.183, so BP4 is met at supporting strength only. SpliceAI max delta score = 0.01 (spliceai) is essentially null, corroborating a benign computational signal from the splice-impact path but is not stacked as additional strength since it reflects the same overall low-impact prediction rather than an independent calibrated line of evidence. BayesDel score -0.300447 (bayesdel) was not used because no verified, citable published calibration threshold for BayesDel is available to this pipeline.
ClinGen SVI calibrated REVEL thresholds (Pejaver et al. 2022, PMID 36413997), BP4 supporting tier, applied under generic ACMG/AMP framework.
This is a missense variant (NM_005378.5:c.926G>T, p.(Gly309Val)). No gene-specific ClinGen VCEP is available for MYCN (case_summary.framework_mode = generic_acmg; vcep_materials.final_classification_framework.found = false), so generic calibrated computational thresholds apply. REVEL score = 0.214 (revel), well below the ClinGen SVI Pejaver et al. 2022 (PMID 36413997) supporting-pathogenic threshold of REVEL >= 0.644, so PP3 is not supported by the missense in-silico predictor. SpliceAI max delta score = 0.01 (spliceai), far below any splice-impact threshold (~0.1-0.2), so the splice-impact path also does not support PP3. BayesDel score of -0.300447 was returned by the local lookup (bayesdel) but no verified published calibration threshold for BayesDel is available to this pipeline, so it is treated as not_available and was not used to score this criterion.
ClinGen SVI calibrated REVEL thresholds (Pejaver et al. 2022, PMID 36413997) applied under generic ACMG/AMP framework; SpliceAI max delta score below splice-impact threshold.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005378.5:c.926G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Gly309Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.214. BayesDel score = -0.300447.
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.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.85861e-06; MAF= 0.00019%, 3/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.68509e-05; MAF= 0.00669%, 3/44876 alleles, homozygotes = 0); grpmax FAF= 1.773e-05.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.214. BayesDel score = -0.300447.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYCN, a transcription factor, is altered by amplification and overexpression in a variety of cancer types including in neuroblastoma.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.