chr12-32843247-CTGGGA-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_004572.4(PKP2):c.1440_1444delTCCCA(p.Asn480LysfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000045 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PKP2
NM_004572.4 frameshift
NM_004572.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.544
Genes affected
PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-32843247-CTGGGA-C is Pathogenic according to our data. Variant chr12-32843247-CTGGGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419977.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=2}. Variant chr12-32843247-CTGGGA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000833 AC: 2AN: 239996Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130518
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000449 AC: 4AN: 891198Hom.: 0 AF XY: 0.00000876 AC XY: 4AN XY: 456664
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GnomAD4 genome 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This sequence change creates a premature translational stop signal (p.Asn480Lysfs*20) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is present in population databases (rs775995156, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25157032). ClinVar contains an entry for this variant (Variation ID: 419977). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2023 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Cardiology unit, Meyer University Hospital | Sep 27, 2022 | - - |
not provided Pathogenic:2Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2017 | This five base pair deletion has been reported previously in the Human Gene Mutation Database and the Arrhythmogenic Right Ventricular Cardiomyopathy database (Stenson et al., 2014; Van et al., 2009). The c.1440_1444delTCCCA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Asparagine 480, changing it to a Lysine, and creating a premature stop codon at position 20 of the new reading frame, denoted p.Asn480LysfsX20. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the PKP2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014). - |
| Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 13, 2018 | The p.Asn480fs variant in PKP2 has been reported in 2 individuals with ARVC, and segregated with disease in 1 affected family member from one family (Brun 2014, www.arvcdatabase.info). However, both individuals also carried other pathogenic variants in genes that could explain their disease. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 419977) and has been identified in 3/123052 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775995156). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 480 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While heterozygous loss of function is an established disease mechanism in individuals with ARVC, this variant is located in an exon that is alternatively spliced and is not present in the dominant transcript in the heart (Gandjbakhch 2011). In summary, the clinical significance of the p.Asn480fs variant is uncertain. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 15, 2023 | This variant deletes 5 nucleotides in exon 6 of the PKP2b transcript (ENST00000070846 NM_004572), creating a frameshift and premature translation stop signal. This exon 6 is alternately spliced out and is absent in the PKP2a transcript, the predominant isoform in the heart (ENST00000340811 NM_001005242, PMID 21378009). Therefore, it is likely that a functional PKP2 gene product is expressed in the heart, despite the presence of this variant. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy, including two from the same family who also carried a pathogenic variant in the DSP gene (PMID: 25157032, 28588093). This variant has been identified in 3/271396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 02, 2022 | This variant deletes 5 nucleotides in exon 6 of the PKP2b transcript (ENST00000070846 NM_004572), creating a frameshift and premature translation stop signal. This exon 6 is alternately spliced out and is absent in the PKP2a transcript, the predominant isoform in the heart (ENST00000340811 NM_001005242, PMID 21378009). Therefore, it is likely that a functional PKP2 gene product is expressed in the heart, despite the presence of this variant. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy, including two from the same family who also carried a pathogenic variant in the DSP gene (PMID: 25157032, 28588093). This variant has been identified in 3/271396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
PKP2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2024 | The PKP2 c.1440_1444del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn480Lysfs*20). This variant was reported in individuals with arrhythmogenic right ventricular cardiomyopathy (Brun et al. 2014. PubMed ID: 25157032; Table S2, Orgeron et al. 2017. PubMed ID: 28588093; Supplementary table 2, van Lint et al. 2019. PubMed ID: 31386562 ). This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. While loss-of-function is an established mechanism for PKP2-assoicated arrhythmogenic right ventricular dysplasia, this variant occurs in an exon which is alternately spliced out and is absent in the isoform that is predominantly expressed in the human heart tissues (referred to as c.1379-2047_1379-2043del5 in the predominantly expressed transcript NM_001005242; Gandjbakhch et al. 2011. PubMed ID: 21378009). Additional evidence is needed to further evaluate loss-of-function variants located in this alternate exon 6. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2024 | The c.1440_1444delTCCCA variant, located in coding exon 6 of the PKP2 gene, results from a deletion of 5 nucleotides at nucleotide positions 1440 to 1444, causing a translational frameshift with a predicted alternate stop codon (p.N480Kfs*20). This variant has been detected in individuals with features consistent with arrhythmogenic cardiomyopathy (Orgeron GM et al. J Am Heart Assoc, 2017 Jun;6; Girolami F et al. Front Cardiovasc Med, 2022 Dec;9:1080608). Frameshift alterations are typically deleterious in nature, and loss of PKP2 function is an accepted mechanism of disease. However, pathogenicity has not been established for alterations in exon 6 of PKP2. The exon is alternatively spliced, and the predominant isoform in human cardiac tissue, PKP2A, does not include exon 6 (Gandjbakhch E et al. Heart. 2011;97(10):844-9). Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at