The PKP2 NM_001005242.3:c.2014-1G>C (NP_001005242.2:p.?) splicing variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to disrupt normal RNA processing, resulting in either an aberrant protein product or nonsense-mediated RNA decay. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PKP2 encodes plakophilin-2, a protein that helps organize cell junctions called desmosomes and supports connections between cell-adhesion proteins and the cell’s internal structural network. It also helps regulate beta-catenin signaling and the expression of genes involved in calcium cycling in heart muscle cells. Inherited PKP2 changes are associated with arrhythmogenic cardiomyopathy, Brugada syndrome, and idiopathic ventricular fibrillation; it has no established role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. 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 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.
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.
Met at supporting: gnomAD v4.1 AF is 7.68405e-05 with grpmax FAF 8.675e-05, below the PM2 threshold of 0.0001.
Met, moderate: SpliceAI max delta 0.983 meets the >=0.5 PP3 threshold for splice-region variants.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1 very strong, PS4 strong, PM2 supporting, and PP3 moderate total 15 points under the PKP2 Expert Panel point-based framework.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 124 / 1,613,732 alleles. Recorded AF 7.68405e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.18392e-05; MAF= 0.00318%, 9/282670 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.97415e-05; MAF= 0.00697%, 9/129048 alleles, homozygotes = 0); grpmax FAF= 3.422e-05.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.983. Refer to the recorded PP3/BP4 rationale for interpretation.
32 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 5 not met · 10 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Generic ACMG/AMP rules govern because the PKP2 CSPEC is listed but has no released criteria.
PVS1 is met at very strong strength for the canonical -1 splice-site variant in a PKP2 loss-of-function disease context; PM4 and BP3 are not applicable because the variant is not an in-frame indel or stop-loss change.
All five requested codon/residue/domain criteria are not applicable because the case variant is a canonical splice-site change, c.2014-1G>C, with protein consequence p.? rather than a translated missense substitution.
The PKP2 VCEP is listed without released criterion specifications for this case; generic ACMG/AMP definitions therefore govern the requested assessments.
For PS2, PM6, PP1, and BS4, the available evidence does not provide the criterion-specific parental or family segregation data needed for a met or not_met determination.
The variant is a canonical splice-acceptor variant; PP3 and BP4 therefore use only the SpliceAI path, while BP7 is outside scope because the variant is not synonymous.
SpliceAI max delta 0.983 meets the supplied PP3 moderate threshold and exceeds the BP4 no-impact threshold; the same prediction is not double-counted across criteria.
Population evidence supports PM2 at supporting strength because the variant's gnomAD filtering allele frequencies are below 0.0001.
BA1 and BS1 are not met because the required grpmax FAF values are far below their generic thresholds.
BS2 is not assessed because aggregate gnomAD carrier data do not establish healthy adult status and PKP2-related disease has age-dependent reduced penetrance.
No criteria match.
NM_001005242.3:c.2014-1G>C is a canonical acceptor splice-site variant at position -1 in PKP2, a gene with established germline loss-of-function disease mechanism. The assessed transcript is the case transcript, and the predicted skipping of exon 10 removes 154 coding nucleotides, shifts the reading frame, and affects an internal exon rather than the last or penultimate exon. These facts support a null consequence through a canonical splice-site disruption under the generic PVS1 framework. No named downgrade rule applies: the variant is not shown to escape NMD, the affected exon is not identified as non-critical, and the consequence is not limited to a distal non-critical region. Therefore PVS1 is met at full strength.
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Met. PMID:21636032 explicitly identifies the exact splice-site variant as PKP2-IVS10-1G>C, corresponding to NM_001005242.3:c.2014-1G>C, in 13 ARVC probands and reports it absent from 427 ostensibly healthy controls in a study of 175 ARVC probands. This is a case-control comparison even though the paper does not print an odds ratio. Using the reported counts (13 variant-positive cases, 162 variant-negative cases, 0 variant-positive controls, 427 variant-negative controls) and the Haldane-Anscombe 0.5 continuity correction for the zero control cell, the calculated OR is 71.03 with an approximate 95% CI of 4.20-1201.84. The governing threshold is OR >5.0 and the confidence interval must not include 1.0: 71.03 > 5.0? yes; 4.20-1201.84 includes 1.0? no. Therefore PS4 is met. The literature_pass packet has no ai_classified_papers; the directly extracted full-text finding for PMID:21636032 was verified and supports this conclusion.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is met at supporting strength under the supplied generic ClinGen SVI threshold. The variant is rare in population controls: gnomAD v4.1 all-comers AF=7.68405e-05 (124/1613732 alleles; 0 homozygotes), with grpmax FAF=8.675e-05; gnomAD v2.1 all-comers AF=3.18392e-05 (9/282670; 0 homozygotes), with grpmax FAF=3.422e-05. The specified non-cancer subsets are also rare: gnomAD v2.1 non-cancer exomes AF=3.37946e-05 (8/236724; 0 homozygotes), grpmax FAF=3.846e-05, and gnomAD v3.1 non-cancer genomes AF=2.70395e-05 (4/147932; 0 homozygotes), grpmax FAF=1.972e-05. No governing VCEP criterion specifies a non-cancer-only source, so the all-comers default applies. The available frequency values are <=0.0001, the supplied PM2 supporting threshold.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a canonical splice-acceptor variant at c.2014-1, so the applicable generic computational path is SpliceAI rather than REVEL. SpliceAI reported a maximum delta score of 0.983 (DS_AL 0.983), which meets the supplied PP3 moderate threshold of >= 0.5. The splice prediction is used only for PP3 and is not also counted for BP4 or BP7.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Not met. ClinVar variation 6756 has exact-variant Pathogenic submissions, but the audit reports 0 expert-panel submissions and identifies the available assertions as ordinary laboratory or otherwise non-expert submissions. The generic PP5 condition is therefore not satisfied; the published evidence is also available for independent evaluation rather than being unavailable to the laboratory.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The required filtering allele frequency is the grpmax FAF rather than the popmax point estimate. gnomAD v4.1 reports grpmax FAF=8.675e-05 (0.008675%) from 124/1,613,732 all-comers alleles; gnomAD v2.1 reports grpmax FAF=3.422e-05, and gnomAD v2.1 non-cancer exomes report grpmax FAF=3.846e-05. These values are all below the generic BA1 stand-alone threshold of >=0.05. No small isolate population qualifies as an alternative because the relevant population must have at least 2,000 observed alleles. The pathogenic ClinVar consensus also means the default frequency threshold cannot be used as a stand-alone benign endpoint without stronger reconciliation.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. Using the required filtering allele frequency, gnomAD v4.1 grpmax FAF=8.675e-05 (0.008675%), gnomAD v2.1 grpmax FAF=3.422e-05, and gnomAD v2.1 non-cancer exome grpmax FAF=3.846e-05 are all below the generic BS1 default of >=0.01. PKP2-related arrhythmogenic cardiomyopathy has reduced, age-dependent penetrance and variable expressivity in the available family study, so the 1% default is not universally decisive; nevertheless, these observed FAF values do not indicate an allele frequency greater than expected for the disorder. No disease-specific maximum-credible-frequency calculation is needed to establish non-application because the filtering frequencies are already substantially below the default threshold.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The variant is a canonical splice-acceptor variant, so the applicable generic computational path is SpliceAI. SpliceAI reported a maximum delta score of 0.983, which is above the supplied BP4 supporting threshold of <= 0.1 and therefore does not support no splice impact. The SpliceAI result is not reused from PP3 as separate evidence.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Not met. The exact-variant ClinVar record contains no expert-panel benign or likely benign classification; the available submissions are Pathogenic laboratory assertions, aggregate labels, or non-expert records. Those records cannot trigger BP6 under the generic rule restriction.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PS2 cannot be assessed from the available evidence. ClinVar contains one submission recording paternal origin, but there is no documented confirmation of both maternity and paternity, no documented exclusion of a family history, and no proband-level de novo segregation report. Paternal origin alone does not establish a de novo event or satisfy the requirement for confirmed maternity and paternity.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No validated functional assay directly evaluated PKP2 c.2014-1G>C. PMID:21636032 reports the exact variant in ARVC cases but provides no RNA, protein, or other functional result for it; PMID:25087486 experimentally assessed different PKP2 splice-site variants and explicitly did not assess c.2014-1G>C. Therefore, the available evidence is insufficient to apply PS3 rather than evidence against a damaging effect.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM6 cannot be assessed from the available evidence. A ClinVar submission records paternal origin, but the record does not establish that the variant was assumed de novo, does not provide parental testing details sufficient to determine the unconfirmed parent status, and does not document the affected proband and family-history context required for this criterion.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed as met because the exact variant was reported in 13 ARVC cases, including four Dutch cases, as a cohort-level observation of unrelated probands. The available report does not provide affected-family genotype/phenotype pairs, informative meioses, or variant-specific co-segregation data. Therefore, the evidence does not establish co-segregation, but it also does not establish contradictory non-segregation.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Not assessed. The available evidence establishes that the exact variant was observed in ARVC probands, but it does not provide the phenotype or family history of the present case and therefore cannot establish that this patient's phenotype is highly specific for a single-gene disease.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD shows heterozygous carrier alleles but no homozygotes, yet aggregate reference-database observations do not establish that any specific carrier was a healthy adult with adequate age and phenotype assessment. PKP2-related arrhythmogenic cardiomyopathy has reduced, age-dependent penetrance and variable expressivity, so the governing requirement of full penetrance at an early age is not established for this disorder. A curated individual-level healthy-adult observation with sufficient age and clinical evaluation would be needed.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No validated functional assay directly evaluated PKP2 c.2014-1G>C and demonstrated a normal effect on protein function or splicing. PMID:21636032 reports the exact variant in ARVC cases without a functional result, while PMID:25087486 tested different PKP2 splice-site variants and did not test c.2014-1G>C. Therefore, BS3 cannot be assessed.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BS4 cannot be assessed because the available evidence contains no variant-specific family data showing affected relatives who lack the variant. The cohort report describes unrelated ARVC probands and does not supply affected-family non-segregation observations. No documented phenocopy or alternate pathogenic-variant analysis is available for this case.
Lack of segregation in affected members of a family.
The evidence reports the exact PKP2 variant in ARVC cases but does not provide parental or offspring testing, haplotyping, or another phase-resolved observation showing the variant in trans with a pathogenic variant or in cis with a pathogenic variant. The dominant disease context alone cannot establish BP2.
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.
Not assessed. No evidence in the supplied case materials establishes that this variant was found in a case with an alternate molecular basis for disease. The ARVC case-control paper concerns this variant's prevalence and does not document an alternate molecular diagnosis for a particular case.
Variant found in a case with an alternate molecular basis for disease.
Not applicable: PS1 requires the same amino acid change as a previously established pathogenic variant, but this case is NM_001005242.3:c.2014-1G>C, a canonical splice-site variant annotated as NP_001005242.2:p.?, with no amino-acid substitution to compare. The governing caveat specifically warns that changes impacting splicing rather than the amino-acid/protein level should not be assessed through PS1.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Not applicable: PM1 concerns location in a mutational hotspot or critical functional domain, but this variant is at the canonical intronic acceptor position c.2014-1 and has no translated amino-acid residue or protein-domain location. The PKP2 domain_tables entry is absent, and no residue-level domain assessment can be made for p.?.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM3 is restricted to recessive disorders and requires the variant to be detected in trans with a pathogenic variant. The case evidence concerns PKP2-related arrhythmogenic right ventricular cardiomyopathy, an established dominant disease context, and provides no evidence that this case represents a recessive PKP2 disorder or a biallelic affected individual; therefore PM3 is not applicable.
For recessive disorders, detected in trans with a pathogenic variant
This variant is a canonical splice-site substitution, not an in-frame deletion, in-frame insertion, or stop-loss variant. Its predicted consequence is exon skipping with a frameshift rather than a directly characterized protein length change of the type named by PM4, so PM4 is outside the governing rule's applicability.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Not applicable: PM5 requires a novel missense change at an amino-acid residue where a different pathogenic missense change has been observed. This case is a canonical splice-site variant, c.2014-1G>C, annotated with protein consequence p.?, so it has neither a missense substitution nor a translated residue for same-residue comparison.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Not applicable: PP2 explicitly requires a missense variant in a gene with a low rate of benign missense variation and missense as a common disease mechanism. This variant is a canonical splice-site change with protein consequence p.?, not a missense variant.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Not applicable: BP1 explicitly requires a missense variant in a gene for which primarily truncating variants are known to cause disease. This case is a canonical splice-site variant, c.2014-1G>C, with protein consequence p.?, not a missense variant.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
This variant is a canonical splice-site substitution, not an in-frame deletion or insertion. The governing BP3 rule therefore does not apply, regardless of repeat-region context, because the required in-frame indel variant type is absent.
In frame-deletions/insertions in a repetitive region without a known function.
BP7 applies only to synonymous variants. NM_001005242.3:c.2014-1G>C is a canonical splice-acceptor variant, not a synonymous coding variant, so BP7 is outside its governing scope regardless of the available SpliceAI score.
BP7: A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Every interpreted variant in PKP2, mapped onto the exon structure of NM_001005242.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)120 / 1,179,788 | 0.0001 |
| Remaining individuals4 / 62,478 | 6.4e-05 |
| European (non-Finnish)9 / 129,048 | 7e-05 |
This variant is present in gnomAD v4.1 (AF= 7.68405e-05; MAF= 0.00768%, 124/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000101713; MAF= 0.01017%, 120/1179788 alleles, homozygotes = 0); grpmax FAF= 8.675e-05.
This variant is present in gnomAD v2.1 (AF= 3.18392e-05; MAF= 0.00318%, 9/282670 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.97415e-05; MAF= 0.00697%, 9/129048 alleles, homozygotes = 0); grpmax FAF= 3.422e-05.
Not available in gnomAD-Canada v1.0.
The variant is a canonical splice-acceptor variant at c.2014-1, so the applicable generic computational path is SpliceAI rather than REVEL. SpliceAI reported a maximum delta score of 0.983 (DS_AL 0.983), which meets the supplied PP3 moderate threshold of >= 0.5. The splice prediction is used only for PP3 and is not also counted for BP4 or BP7.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a canonical splice-acceptor variant, so the applicable generic computational path is SpliceAI. SpliceAI reported a maximum delta score of 0.983, which is above the supplied BP4 supporting threshold of <= 0.1 and therefore does not support no splice impact. The SpliceAI result is not reused from PP3 as separate evidence.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 applies only to synonymous variants. NM_001005242.3:c.2014-1G>C is a canonical splice-acceptor variant, not a synonymous coding variant, so BP7 is outside its governing scope regardless of the available SpliceAI score.
BP7: A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.98). BayesDel score = 0.66.
9 paper records listed. 2 cited in the classification.
PKP2-IVS10−1G>C which was identified in 13 ARVC cases (four Dutch)
Location Results, Founder Mutations
Context Targeted sequencing of splice-site regions and coding exons in 175 ARVC probands from Dutch and North American cohorts, with comparison to 427 ostensibly healthy controls.
For splice site variants, the variant may lead to exon skipping, shortening or inclusion of intronic material, due to alternative donor/acceptor site usage or creation of new sites. Although splice site variants are predicted to lead to a null effect, confirmation of impact requires functional analysis by either RNA or protein analysis.
Location Proposed Criteria for Interpretation of Sequence Variants, PVS1 Null variants
Context General ACMG/AMP variant-classification guideline; no PKP2-specific cohort or assay described.
Among the 39 individuals identified as mutation carriers, 19 (49%) met the 1994 Task Force criteria for ARVD/C.
Results, Prevalence of ARVD/C in PKP2 mutation carriers
In vitro mRNA analyses confirmed the spliceogenic effect of all 3 intronic PKP2 variants (c.1511-2A4G, c.2146-1G4C, c.2578-3A4G), indicating the pathogenic character of these variants.
Results, PKP2 variants; Table 2; Discussion
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= 7.68405e-05; MAF= 0.00768%, 124/1613732 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000101713; MAF= 0.01017%, 120/1179788 alleles, homozygotes = 0); grpmax FAF= 8.675e-05.
This variant is present in gnomAD v2.1 (AF= 3.18392e-05; MAF= 0.00318%, 9/282670 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.97415e-05; MAF= 0.00697%, 9/129048 alleles, homozygotes = 0); grpmax FAF= 3.422e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories). (ClinVarID = 6756)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.98). BayesDel score = 0.66.
This variant has not previously been reported in somatic cancers (COSMIC).