Variant classification summary

NM_001005242.3:c.2014-1G>C

PKP2 · NP_001005242.2:p.? · NM_001005242.3

GRCh37: chr12:32955491 C>G · GRCh38: chr12:32802557 C>G

Gene: PKP2 Transcript: NM_001005242.3

Final call

Pathogenic

PVS1 very strong PS4 strong PM2 supporting PP3 moderate

Variant details

Gene

PKP2

Transcript

NM_001005242.3

Protein

NP_001005242.2:p.?

gnomAD AF

7.684051626912027e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports a null splice consequence in the PKP2 loss-of-function disease mechanism.

2

Pathogenic: PS4 strong is supported by 13 cases and 0 controls, with continuity-corrected OR 71.03.

3

Pathogenic: PM2 supporting is met because gnomAD v4.1 filtering AF 8.675e-05 is below 0.0001.

4

Pathogenic: PP3 moderate is met because SpliceAI maximum delta 0.983 predicts splice disruption.

Final determination: Under the PKP2 Expert Panel Version 1.0 point-based framework, 15 points from PVS1 very strong, PS4 strong, PM2 supporting, and PP3 moderate meet the >=10-point Pathogenic rule.

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 at very strong: canonical -1 splice variant with predicted exon-10 skipping removes 154 coding nucleotides and shifts the reading frame in LOF-mechanism gene PKP2.	PMID:21636032 PMID:25741868
PS1	N/A	Not applicable: c.2014-1G>C is a canonical splice-site variant with protein consequence p.?, so no same-amino-acid change exists for PS1.
PS2	Not assessed	Not assessed: only paternal origin is documented, with no confirmed maternity and paternity, family-history assessment, or proband-level de novo report.	clinvar
PS3	Not assessed	Not assessed: the exact variant was reported in 13 ARVC cases, but no validated RNA, protein, or other functional assay directly tested c.2014-1G>C.	PMID:21636032 PMID:25087486
PS4	Met	Met: exact variant occurred in 13 ARVC cases and 0 controls, yielding continuity-corrected OR 71.03 (95% CI 4.20-1201.84) versus the >5.0 threshold.	PMID:21636032
PM1	N/A	Not applicable: the variant is a canonical intronic splice-site change, c.2014-1G>C, with no translated residue to place in a functional domain.
PM2	Met	Met at supporting: gnomAD v4.1 AF is 7.68405e-05 with grpmax FAF 8.675e-05, below the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:21636032 PMID:25741868
PM3	N/A	Not applicable: PM3 requires a recessive disorder with the variant proven in trans with a pathogenic variant, but this case provides no recessive or biallelic PKP2 evidence.	PMID:21636032
PM4	N/A	Not applicable: c.2014-1G>C is a canonical splice-site substitution predicted to cause exon skipping and frameshifting, not an in-frame indel or stop-loss variant.
PM5	N/A	Not applicable: c.2014-1G>C is a canonical splice-site variant with protein consequence p.?, not a novel missense change at a defined amino-acid residue.
PM6	Not assessed	Not assessed: paternal origin is recorded, but an assumed de novo event and the required proband and parental context are not documented.	clinvar
PP1	Not assessed	Not assessed: the exact variant occurred in 13 ARVC cases, but no affected-family co-segregation or informative meiosis count is documented.	PMID:21636032
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas c.2014-1G>C is a canonical splice-site variant with protein consequence p.?.
PP3	Met	Met, moderate: SpliceAI max delta 0.983 meets the >=0.5 PP3 threshold for splice-region variants.	spliceai
PP4	Not assessed	Not assessed: the present case's phenotype and family history are unavailable, so specificity for a single genetic etiology cannot be determined.
PP5	Not met	Not met: ClinVar shows Pathogenic laboratory submissions but 0 expert-panel submissions, and the underlying evidence is available for independent evaluation.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8.675e-05, far below the generic BA1 stand-alone threshold of 0.05.	gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8.675e-05, below the generic BS1 default threshold of 0.01.	gnomad_v2 gnomad_v4 PMID:17010805
BS2	Not assessed	Not assessed: gnomAD shows no homozygotes, but carrier age and phenotype are unavailable and PKP2 disease has age-dependent reduced penetrance.	gnomad_v2 gnomad_v4 PMID:17010805
BS3	Not assessed	Not assessed: no validated functional assay directly showed that PKP2 c.2014-1G>C has no damaging effect on protein function or splicing.	PMID:21636032 PMID:25087486
BS4	Not assessed	Not assessed: no affected-relative genotype/phenotype pairs or documented variant-specific non-segregation are available.
BP1	N/A	Not applicable: BP1 requires a missense variant, but c.2014-1G>C is a canonical splice-site variant with protein consequence p.?.
BP2	Not assessed	Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic variant in the reported ARVC cases.	PMID:21636032
BP3	N/A	Not applicable: c.2014-1G>C is a splice-site substitution, not an in-frame deletion or insertion required for BP3, so repeat-region context cannot invoke the criterion.
BP4	Not met	Not met: SpliceAI max delta 0.983 exceeds the <=0.1 BP4 threshold for no predicted splice impact.	spliceai
BP5	Not assessed	Not assessed: no case is documented with this variant plus an independent alternate molecular basis for the disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; available submissions are non-expert Pathogenic assertions.	clinvar
BP7	N/A	Not applicable: this is a canonical splice-acceptor variant, not a synonymous variant required for BP7.

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