NM_004562.2(PRKN):c.1204C>T

PRKN · NP_004553.2:p.(Arg402Cys) · NM_004562.2

GRCh37: chr6:161781201 G>A · GRCh38: chr6:161360169 G>A

Gene: PRKN Transcript: NM_004562.2

Final call

Likely Benign

BS2 strong benign BP4 supporting benign

Variant details

Gene

PRKN

Transcript

NM_004562.2

Protein

NP_004553.2:p.(Arg402Cys)

gnomAD AF

0.001856078346826453 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant has been observed in the homozygous state in population databases (4 homozygotes in gnomAD v2.1, 12 homozygotes in gnomAD v4.1), meeting BS2 (strong benign) for an autosomal recessive early-onset Parkinson disease with full penetrance.

Multiple lines of computational evidence suggest no deleterious impact: BayesDel score 0.144 is in the benign range, SpliceAI predicts no splicing effect (max delta 0.0), and REVEL score 0.627 is indeterminate. Meeting BP4 at supporting benign level.

Combination of BS2 (strong benign) and BP4 (supporting benign) meets the generic ACMG/AMP 2015 threshold for Likely Benign (1 Strong benign + 1 Supporting benign).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Missense variant (c.1204C>T, p.Arg402Cys) does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). Generic PVS1 framework not applicable per pvs1_variant_assessment.json.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No evidence of a different nucleotide change at c.1204 resulting in the same amino acid change (p.Arg402Cys) that has been independently classified as pathogenic.
PS2	Not met	No de novo observation reported for this variant. No publications or ClinVar submissions provide de novo evidence.	PMID:23279440
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for this variant. No publications with functional data were retrieved.	oncokb
PS4	Not met	No case-control or enrichment data demonstrating increased prevalence of this variant in affected individuals versus controls. The variant has an overall allele frequency of 0.187% in gnomAD v2.1, which is inconsistent with a rare pathogenic variant for autosomal recessive early-onset Parkinson disease. Screen_PS4 passed zero publications.	gnomad_v2
PS5	Not met	No evidence of a second pathogenic variant in trans identified for this recessive disorder. No patient-level genotype data available to assess allelic configuration.
PM1	Not met	Residue Arg402 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No ClinGen-specified critical functional domain data available for PRKN residue 402 in the case materials.
PM2	Not met	Variant allele frequency in gnomAD v2.1 is 0.187% (529/282892 alleles), which exceeds the 0.1% threshold for PM2 under generic ACMG framework.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue comparator variants identified. PM5 candidate harvesting returned zero candidates; unable to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not met	No de novo observation reported. No publications or clinical submissions document a confirmed de novo event for this variant.
PP1	Not met	No segregation data available. No family studies demonstrating cosegregation of c.1204C>T with disease phenotype.	PMID:24816432
PP2	Not met	PRKN missense variants can be pathogenic (loss-of-function) via the ubiquitin-proteasome pathway, and this variant has high population frequency with multiple homozygotes, indicating the gene tolerates benign missense variation. Both criteria for PP2 (low rate of benign missense AND missense as common disease mechanism) are not jointly satisfied for this gene.	gnomad_v2 gnomad_v4 pvs1_gene_context
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.627 is in the indeterminate range (above 0.5 but below typical pathogenic thresholds of 0.7-0.75). BayesDel 0.144 is in the benign range. SpliceAI delta 0.0 predicts no splicing impact. In silico tools are discordant and do not collectively support pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data available to assess whether the individual's clinical presentation is highly specific for PRKN-related disease.
PP5	Not met	ClinVar classification is Likely benign (2 clinical laboratories), Benign (1), and Uncertain significance (1), with 1-star review status ('criteria provided, conflicting classifications'). Under the user-specified framework, PP5 requires ClinVar 3-star expert panel review. ClinVar Variation ID 425402 has only 1-star status and conflicting classifications.	clinvar
BA1	Not met	Overall allele frequency in gnomAD v2.1 is 0.187%, which is below the 1% threshold for BA1 under generic ACMG framework.	gnomad_v2 gnomad_v4
BS1	Not met	Overall allele frequency in gnomAD v2.1 is 0.187% (grpmax FAF 0.214%), which is below the 0.3% threshold for BS1 under generic ACMG framework.	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in the homozygous state in population databases: 4 homozygotes in gnomAD v2.1 and 12 homozygotes in gnomAD v4.1. For autosomal recessive early-onset Parkinson disease (ARJP) caused by biallelic PRKN pathogenic variants, the presence of multiple homozygous individuals in general population databases constitutes strong evidence for a benign classification.	gnomad_v2 gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease. The only segregation-themed publication (PMID:24816432) describes SYNJ1 mutation segregation, not PRKN.	PMID:24816432
BP1	N/A	PRKN pathogenic variants include both missense and truncating changes; the gene is not one in which only truncating variants cause disease.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a known dominant pathogenic variant. No allelic phase data available.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score 0.144 is in the clearly benign range. SpliceAI predicts no splicing impact (max delta = 0.0). REVEL score 0.627 is in the indeterminate zone but does not reach a pathogenic threshold. Preponderance of in silico evidence supports a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No evidence of an alternate molecular basis for disease in a case harboring this variant. No clinical case data with alternative diagnoses available.
BP6	Not met	ClinVar classification for this variant is Likely benign (2 labs) / Benign (1 lab) / VUS (1 lab) with 1-star review status ('criteria provided, conflicting classifications'). Under the user-specified framework, BP6 requires ClinVar 3-star expert panel review. ClinVar Variation ID 425402 has only 1-star status and conflicting classifications; it does not meet the 3-star EP requirement.	clinvar
BP7	N/A	c.1204C>T is a missense variant (p.Arg402Cys), not a synonymous/silent variant. BP7 applies only to synonymous variants with no predicted splice impact.

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