Variant classification summary

NM_004572.4:c.2146-1G>C

PKP2 · NP_004563.2:p.? · NM_004572.4

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

Gene: PKP2 Transcript: NM_004572.4

Final call

Pathogenic

PVS1 very strong PS3 strong PS4 strong PM2 supporting PP3 moderate

Variant details

Gene

PKP2

Transcript

NM_004572.4

Protein

NP_004563.2:p.?

gnomAD AF

7.684051626912027e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports loss of function from canonical splice disruption with predicted exon 11 frameshifting.

2

Pathogenic: PS3 strong confirms exon 11 skipping and a frameshifted transcript in variant-specific RNA studies.

3

Pathogenic: PS4 strong shows 13 affected cases versus no controls, with a corrected OR of 71.03.

4

Pathogenic: PM2 supporting shows an extremely low gnomAD frequency and zero homozygotes.

5

Pathogenic: PP3 moderate shows a SpliceAI max delta of 0.983.

Final determination: Under the PKP2 Version 1.0 point-based framework, a total of 19 points from PVS1 very strong, PS3 strong, PS4 strong, PM2 supporting, and PP3 moderate meets the Pathogenic threshold of at least 10 points.

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 loss predicts exon 11 skipping and a frameshift in exon 11 of 14, without an NMD-escape downgrade.	pvs1_generic_framework PMID:25741868 PMID:21636032
PS1	N/A	Not applicable: c.2146-1G>C is a canonical splice variant with protein consequence p.?, not a same-amino-acid substitution.	cspec
PS2	Not assessed	Not assessed: no documented parental genotypes or confirmed maternity and paternity establish that the variant is de novo.	PMID:16415378
PS3	Met	Met, strong: variant-specific RT-PCR and Sanger sequencing demonstrated exon 11 skipping and a frameshift transcript, with normal controls and approximately 1:1 allele expression.	PMID:25087486
PS4	Met	Met: 13/175 cases versus 0/427 controls gives Haldane-corrected OR 71.03 (95% CI 4.20-1201.84), exceeding the OR >5.0 threshold with a CI excluding 1.0.	PMID:21636032
PM1	N/A	Not applicable: the canonical splice variant has no assigned protein residue, and PKP2's authoritative domain table contains no approved domain route.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 grpmax FAF is 8.675e-05, below the supplied PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2 PMID:21636032 PMID:25741868
PM3	N/A	Not applicable: PKP2-associated arrhythmogenic right ventricular cardiomyopathy is autosomal dominant, whereas PM3 is restricted to recessive disorders.	cspec PMID:21636032
PM4	N/A	Not applicable: this canonical splice-site substitution is neither an in-frame indel nor a stop-loss variant, the only protein-length changes named by PM4.
PM5	N/A	Not applicable: c.2146-1G>C has protein consequence p.?, so no amino-acid residue exists for a different-pathogenic-missense comparison.	cspec
PM6	Not assessed	Not assessed: a proband without known family history is reported, but no evidence supports an assumed de novo event without parental confirmation.	PMID:16415378
PP1	Not assessed	Not assessed: the variant appears in 13 unrelated ARVC cases, but no informative family-level cosegregation or meiosis count is provided.	PMID:16415378 PMID:21636032
PP2	N/A	Not applicable: PP2 is restricted to missense variants, while c.2146-1G>C is a canonical splice-acceptor variant with protein consequence p.?.	cspec
PP3	Met	Met at moderate strength: SpliceAI max delta 0.983 exceeds the >=0.5 threshold for splice-impact evidence.	spliceai
PP4	Not assessed	Not assessed: the available record lacks the individual patient's phenotype or family history needed to judge specificity for a single genetic etiology.
PP5	Not met	Not met: ClinVar has 0 expert-panel submissions for the exact variant, so ordinary pathogenic laboratory assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.008675%, far below the 5% BA1 stand-alone threshold.	gnomad_v4 gnomad_v2 clinvar PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.008675%, below the generic 1% BS1 default.	gnomad_v4 gnomad_v2 PMID:21636032
BS2	Not met	Not met: no healthy adult carrier is documented, and PKP2-associated ARVC has incomplete penetrance rather than established early full penetrance.	gnomad_v4 gnomad_v2 PMID:21636032
BS3	Not met	Not met: the exact variant caused exon 11 skipping and a frameshifted PKP2 transcript rather than showing no damaging effect on splicing.	PMID:25087486
BS4	Not assessed	Not assessed: no affected relative is documented as variant-negative, and the reported family had no additional members available for screening.	PMID:16415378
BP1	N/A	Not applicable: BP1 is restricted to missense variants, but c.2146-1G>C is a canonical splice-acceptor variant with protein consequence p.?.	cspec
BP2	Not assessed	Not assessed: 13 ARVC cases were reported, but no cis/trans phase result or pathogenic allele in cis/trans was documented.	cspec PMID:21636032
BP3	N/A	Not applicable: the variant is a canonical splice-site substitution, not an in-frame deletion or insertion in a repetitive region as required by BP3.
BP4	Not met	Not met: SpliceAI max delta 0.983 is above the <=0.1 threshold required for BP4 supporting evidence.	spliceai
BP5	Not met	Not met: no alternate molecular basis for the disease is reported for this case.
BP6	Not met	Not met: no exact-variant ClinVar Expert Panel benign or likely benign classification is available to trigger BP6.	clinvar
BP7	N/A	Not applicable: the variant is a canonical splice-site change, whereas BP7 applies only to synonymous variants.

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