rs775995156

Positions:

• chr12-32843247-CTGGGA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000070846.11(PKP2):​c.1440_1444del​(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 ENST00000070846.11 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:5
• 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]

ACMG classification

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: {Likely_pathogenic=2, Uncertain_significance=4, Pathogenic=1}. Variant chr12-32843247-CTGGGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1379-2047_1379-2043del		intron_variant		ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1379-2047_1379-2043del		intron_variant		1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000833 AC: 2 AN: 239996 Hom.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 130518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000449 AC: 4 AN: 891198 Hom.: 0 AF XY: 0.00000876 AC XY: 4 AN XY: 456664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.0000299

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:5

Revision: criteria provided, conflicting classifications

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 variant is present in population databases (rs775995156, gnomAD 0.002%). 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 premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25157032). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419977). -
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:2 Uncertain:1

Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
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). -
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. -

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. -

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. -

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

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775995156; hg19: chr12-32996181;