Variant classification summary

NM_000321.2:c.2439dupT

RB1 · NP_000312.2:p.(Lys814Ter) · NM_000321.2

GRCh37: chr13:49039453 A>AT · GRCh38: chr13:48465317 A>AT

Gene: RB1 Transcript: NM_000321.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

RB1

Transcript

NM_000321.2

Protein

NP_000312.2:p.(Lys814Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: RB1 c.2439dup creates p.Lys814Ter and is predicted to undergo nonsense-mediated decay.

2

PM2 supporting: c.2439dupT is absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one supporting pathogenic criterion supports Likely Pathogenic.

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	Met, very strong: RB1 c.2439dup creates p.Lys814Ter in exon 23 of 27, predicting NMD and loss of 116 of 929 amino acids.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:22205104
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotypes or confirmed maternity and paternity establish de novo occurrence of NM_000321.2:c.2439dupT.
PS3	Not assessed	Not assessed: no validated functional assay tested RB1 c.2439dup or p.Lys814Ter, so variant-specific damaging evidence is unavailable.
PS4	Not assessed	Not assessed: no variant-specific case-control counts or enrichment statistic were available to evaluate PS4.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: variant absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 requires a recessive disorder with a pathogenic variant in trans, but RB1 predisposition is heterozygous rather than recessive.
PM4	N/A	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_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). 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.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband-level report documents apparently de novo NM_000321.2:c.2439dupT without parental testing.
PP1	Not assessed	Not assessed: zero informative meioses or affected relatives are documented for segregation of NM_000321.2:c.2439dupT.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.2439dup is a truncating variant predicted as p.(Lys814Ter), outside PP3's missense and splice-region/intronic scope.
PP4	Not assessed	Not assessed: no individual clinical phenotype was available to determine whether it is highly specific for an RB1-related disorder.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic/Likely pathogenic classification for c.2439dupT.	clinvar
BA1	Not met	Not met: variant absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: variant absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented unaffected carriers or homozygotes are available to evaluate the BS2 requirement.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign functional assay tested RB1 c.2439dup or p.Lys814Ter with appropriate controls.
BS4	Not assessed	Not assessed: no tested unaffected relatives or informative non-segregation observations are documented for NM_000321.2:c.2439dupT.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic variant or documented cis/trans phase is available for this RB1 variant.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). 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.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.2439dup is a truncating variant predicted as p.(Lys814Ter), outside BP4's missense and splice-region/intronic scope.
BP5	Not assessed	Not assessed: no alternate pathogenic variant or established alternative molecular explanation was documented for the phenotype.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign/Likely benign classification for c.2439dupT.	clinvar
BP7	N/A	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_000321.2:c.2439dup in RB1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000312.2:p.(Lys814Ter). 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.	generic_acmg_combination_rules

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