The PKP2 NM_004572.4:c.2146-1G>C (NP_004563.2: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. Experimental evidence: Variant-specific RT-PCR and Sanger sequencing demonstrated exon 11 skipping and a frameshift transcript, with normal controls and approximately 1:1 allele expression. 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 loss predicts exon 11 skipping and a frameshift in exon 11 of 14, without an NMD-escape downgrade.
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.
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.
Met at supporting: gnomAD v4.1 grpmax FAF is 8.675e-05, below the supplied PM2 threshold of 0.0001, with zero homozygotes.
Met at moderate strength: SpliceAI max delta 0.983 exceeds the >=0.5 threshold for splice-impact evidence.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1 very strong, PS3 strong, PS4 strong, PM2 supporting, and PP3 moderate total 19 points under the PKP2 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: 5 met · 8 not met · 6 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength because the variant affects the canonical -1 splice acceptor, predicted exon 11 skipping causes a frameshift, exon 11 is not terminal or penultimate, and PKP2 loss of function is a known disease mechanism.
PM4 and BP3 are not applicable because the variant is a splice-site single-nucleotide substitution rather than an in-frame indel or stop-loss variant.
All five requested codon/residue/domain criteria are not applicable because the variant is a canonical splice-acceptor change with protein consequence p.?; no amino-acid substitution or missense allele is being evaluated.
PS4 is met from a directly verified exact-variant case-control comparison: 13 affected probands versus 0 controls, with Haldane-corrected OR 71.03 and 95% CI 4.20-1201.84.
PP4 is not assessed because individual phenotype and family-history information is unavailable.
PP5 and BP6 are not triggered because ClinVar reports zero exact-variant Expert Panel submissions; ordinary submissions and aggregate labels are excluded.
BP5 is not met because no alternate molecular basis for disease is documented.
The variant is a canonical splice-site acceptor change; PP3 and BP4 were evaluated through the SpliceAI path only, and BP7 is outside scope because the variant is not synonymous.
No criteria match.
NM_004572.4:c.2146-1G>C is a canonical splice-acceptor (-1) variant in the relevant PKP2 transcript. The affected exon is exon 11 of 14; skipping the 154-nucleotide exon is predicted to shift the reading frame, and the exon is neither the last nor penultimate exon, so the predicted truncating transcript is not expected to escape NMD. PKP2 loss of function is supported as a germline disease mechanism in the case evidence. The variant therefore meets generic PVS1 at full strength without a named downgrade for NMD escape, a non-critical distal exon, or exon-specific population loss-of-function tolerance.
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.
PS3 is met at strong strength. Groeneweg et al. directly evaluated the exact PKP2 c.2146-1G>C splice-acceptor variant in RNA from a variant carrier using RT-PCR, agarose-gel sizing, and Sanger sequencing, with a normal control and confirmation of approximately 1:1 wild-type and mutant transcripts. The mutant transcript showed exon 11 skipping (r.2146_2299del; p.(Met716fs)), producing a frameshift. The assay was biologically relevant to the canonical splice-site variant and included experimental confirmation rather than prediction alone. The study notes that blood-derived RNA may not fully represent cardiac splicing and that in vitro testing alone is not definitive, but the direct, variant-specific, reproducible molecular result is strongly supportive of a damaging effect on PKP2 splicing.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PMID:21636032 directly reports the exact variant under the equivalent notation PKP2-IVS10-1G>C in 13 of 175 ARVC probands and absent from 427 ostensibly healthy controls. This is a case-control comparison even though the paper does not print an odds ratio. Using a Haldane-Anscombe 0.5 correction for the zero control count, the estimated OR is 71.03 with 95% CI 4.20-1201.84; OR 71.03 >= 5.0? yes, and the CI does not include 1.0, so the ACMG/AMP PS4 threshold is met.
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-based threshold. The variant is present at an extremely low frequency in the default all-comers sources: gnomAD v4.1 total AF 7.68405e-05 (124/1,613,732 alleles; homozygotes=0), with grpmax FAF=8.675e-05, and gnomAD v2.1 total AF 3.18392e-05 (9/282,670 alleles; homozygotes=0), with grpmax FAF=3.422e-05. Both filtering FAF values are <=0.0001, the supplied PM2 supporting threshold. No released VCEP rule specifies a non-cancer or exome-only subset for this case, so the all-comers gnomAD entries are the applicable defaults. The exact variant was also absent from 427 ostensibly healthy controls in the cited ARVC study.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is a canonical splice-site acceptor variant, so the applicable computational path is SpliceAI only; REVEL is not applicable and the BayesDel score has no generic ACMG calibration. SpliceAI max delta is 0.983, which meets the supplied PP3 moderate threshold of >= 0.5 (Jaganathan et al. 2019, PMID:30661751).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
ClinVar contains pathogenic exact-variant submissions, but the record reports zero expert-panel submissions; the pathogenic assertions are ordinary laboratory or other non-expert submissions. Under the required generic rule, these assertions cannot trigger PP5.
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. No released PKP2 VCEP criterion rule governs this assessment, so the generic ACMG/AMP threshold applies. The relevant filtering frequency is the gnomAD v4.1 grpmax FAF of 8.675e-05 (0.008675%), based on a population with 1,179,788 observed alleles; this is far below the generic BA1 stand-alone threshold of 0.05. gnomAD v2.1 is also far below the threshold with grpmax FAF=3.422e-05. The low frequency is concordant with the available pathogenic consensus, so there is no frequency-versus-pathogenic-consensus conflict requiring BA1 not_assessed.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The governing definition asks whether the allele frequency is greater than expected for the disorder; the supplied generic default is 0.01, while maximum-credible-frequency assessment is preferred when prevalence, penetrance, and allelic heterogeneity could permit higher frequencies. The relevant gnomAD v4.1 filtering grpmax FAF is 8.675e-05 (0.008675%), well below 0.01, and gnomAD v2.1 is lower at 3.422e-05. The frequency is not elevated in a small isolate population, so the reduced penetrance and variable expressivity reported for PKP2-associated ARVC do not change the conclusion at this frequency.
Allele frequency is greater than expected for the disorder.
BS2 is not met. The generic ACMG/AMP definition requires observation in a healthy adult individual in the relevant inheritance context, with full penetrance expected at an early age. gnomAD v4.1 and v2.1 each report zero homozygotes, and the available case-control study reports the exact variant absent from 427 ostensibly healthy controls rather than documenting a healthy adult carrier. In addition, PMID:21636032 describes familial ARVC as having incomplete penetrance and variable expressivity, so the full-penetrance early-age premise is not established for this disorder. The evidence does not satisfy BS2.
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.
BS3 is not met. The available variant-specific functional study did not show preserved protein function or normal splicing; instead, it demonstrated exon 11 skipping and a frameshifted PKP2 transcript. No independent well-established assay showing no damaging effect on PKP2 function or splicing was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a canonical splice-site acceptor variant, so the applicable computational path is SpliceAI only; REVEL is not applicable. SpliceAI max delta is 0.983, which does not meet the supplied BP4 supporting threshold of <= 0.1 (Jaganathan et al. 2019, PMID:30661751), and the BayesDel score is not usable because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
No evidence identifies an alternate molecular basis for the disease in this case. The available literature and ClinVar material document the variant in ARVC-related cohorts but do not report a competing molecular diagnosis for the case.
Variant found in a case with an alternate molecular basis for disease.
ClinVar contains no exact-variant Expert Panel benign or likely benign classification; the available record instead contains pathogenic or non-expert assertions. Under the required generic rule, ordinary submissions and aggregate labels cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available literature identifies the variant in affected ARVC probands, including a family-J proband without a known family history, but does not document testing of both biological parents, confirmed maternity and paternity, or a demonstrated de novo origin. The PS2 requirements therefore cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The evidence does not establish an assumed de novo event. One paper describes a proband with no known family history, but no parental testing, maternity or paternity information, or explicit de novo inference is provided. PM6 therefore cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
The exact variant is reported in multiple affected ARVC probands, including 13 unrelated cases in one cohort, but the available evidence does not provide variant-positive affected relatives, variant-negative unaffected relatives, family-level meioses, or a count of informative segregations. Reports of multiple affected unrelated individuals are not sufficient to establish cosegregation in multiple affected family members.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The available evidence documents ARVC cohorts and variant observations but does not provide the individual case's phenotype or family history. Therefore, specificity of this patient's phenotype for a single genetic etiology cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
No affected family member is documented to lack the variant. The family-J report states that no additional family members were available for screening, and the unrelated-case cohort does not provide family non-segregation data. Therefore, lack of segregation in affected family members cannot be established.
Lack of segregation in affected members of a family.
The exact variant is reported in 13 ARVC cases, but the available report describes unrelated probands and does not document a pathogenic second variant in the same proband, cis/trans phase, parental testing, or offspring testing. The trans branch of BP2 additionally requires a fully penetrant dominant disorder, whereas the reviewed PKP2/ARVC context is described as incompletely penetrant. The cis branch remains assessable in principle for any inheritance pattern, but no cis observation is documented; BP2 therefore cannot be assigned.
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.
PS1 is not applicable because NM_004572.4:c.2146-1G>C is a canonical splice-acceptor variant with protein consequence p.? rather than an established amino-acid substitution. The rule specifically concerns the same amino-acid change, and its caveat requires avoiding application when the change impacts splicing rather than the amino-acid/protein level.
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.
PM1 is not applicable because the variant is a canonical intronic splice-acceptor change with no assigned protein residue to place in a mutational hotspot or critical functional domain. The authoritative vcep_materials.json domain_tables entry for PKP2 is empty, and no released PKP2 criterion specification supplies a hotspot or domain route.
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. The available PKP2 disease context identifies arrhythmogenic right ventricular cardiomyopathy as autosomal dominant, and the reviewed exact-variant study describes ARVC as having autosomal dominant inheritance with incomplete penetrance. Therefore the recessive-disorder PM3 rule does not apply, regardless of the absence of documented phase with another allele.
PM3: For recessive disorders, detected in trans with a pathogenic variant
PM4 is not applicable because this is a canonical splice-site substitution, not an in-frame deletion, in-frame insertion, or stop-loss variant; no protein-length change of a PM4-specified type is established.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
PM5 is not applicable because this is a canonical splice-acceptor variant with protein consequence p.? and therefore no missense amino-acid residue at which to compare a different pathogenic missense change. The rule's caveat also excludes relying on comparisons when the change impacts splicing rather than the amino-acid/protein level.
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.
PP2 is not applicable because the rule is restricted to missense variants, whereas NM_004572.4:c.2146-1G>C is a canonical splice-acceptor variant with protein consequence p.?; no missense mechanism assessment can be applied to this allele.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
BP1 is not applicable because the rule is restricted to missense variants, whereas NM_004572.4:c.2146-1G>C is a canonical splice-acceptor variant with protein consequence p.?; the gene-level predominance of truncating disease variants cannot be used for this non-missense allele under BP1.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP3 is not applicable because the variant is a canonical splice-site single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region; repeat-region context cannot activate this criterion.
In frame-deletions/insertions in a repetitive region without a known function.
BP7 is limited to synonymous variants. NM_004572.4:c.2146-1G>C is a canonical splice-site acceptor variant, not a synonymous variant, so BP7 is outside its governing scope regardless of the available SpliceAI score.
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_004572.4. 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-site acceptor variant, so the applicable computational path is SpliceAI only; REVEL is not applicable and the BayesDel score has no generic ACMG calibration. SpliceAI max delta is 0.983, which meets the supplied PP3 moderate threshold of >= 0.5 (Jaganathan et al. 2019, PMID:30661751).
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-site acceptor variant, so the applicable computational path is SpliceAI only; REVEL is not applicable. SpliceAI max delta is 0.983, which does not meet the supplied BP4 supporting threshold of <= 0.1 (Jaganathan et al. 2019, PMID:30661751), and the BayesDel score is not usable because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 is limited to synonymous variants. NM_004572.4:c.2146-1G>C is a canonical splice-site acceptor variant, not a synonymous variant, so BP7 is outside its governing scope regardless of the available SpliceAI score.
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. 3 cited in the classification.
PKP2-IVS10–1G>C which was identified in 13 ARVC cases (four Dutch)
Location Results, Founder Mutations paragraph
Context Sanger sequencing of PKP2 and other ARVC-associated genes in 175 ARVC probands from Dutch and North American cohorts, compared with 427 ostensibly healthy controls.
RT-PCR analyses in combination with Sanger sequence analysis revealed exclusion of exons 7 and 11, respectively (exon skipping), leading to shifts in the reading frame of the resulting mutant transcripts (Figures 2B–D and Online Supplemental Figure 2). ... Patient sample shows a mix (ratio ~ 1:1) of PCR products from wild-type and mutant PKP2 alleles. PCR products from the normal allele show exon 10 to exon 11 transition. PCR products from the mutated allele show exon 10 to exon 12 transition, with skipping of exon 11.
Location Results, PKP2 variants; Table 2; Figure 2B–D
Context Nine potential splice-site variants in desmosomal genes were studied in ARVD/C patients; total RNA from fresh peripheral-blood samples was analyzed by RT-PCR, agarose-gel electrophoresis, and direct Sanger sequencing, with normal controls and allele-specific transcript comparison.
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/CAP sequence-variant interpretation guidance; no variant-specific PKP2 assay was reported in this paper.
These included mutations in exons 1 and 11 (145_148delCAGA and 2146-1G3C in families I and J) and 2 missense mutations (S140F and S615F) detected in families G and H, respectively (Figure 1D). ... In family J, the proband has a known mutation in exon 11. He presented at 14 years of age with a syncopal episode and was found to have precordial T-wave inversion, RV enlargement with mildly impaired systolic function, and frequent ventricular ectopy of RV origin. There is no known family history of premature cardiac death. In the absence of family history, he does not fulfill diagnostic criteria.
Results, PKP2 Mutations in Families With ARVC, family J; Table 1
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).