chr12-32878545-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001005242.3(PKP2):​c.337-2A>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000137 in 1,457,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 splice_acceptor

Scores

2
4
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.55
Variant links:
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 16 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 12-32878545-T-A is Pathogenic according to our data. Variant chr12-32878545-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32878545-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKP2NM_001005242.3 linkuse as main transcriptc.337-2A>T splice_acceptor_variant ENST00000340811.9 NP_001005242.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKP2ENST00000340811.9 linkuse as main transcriptc.337-2A>T splice_acceptor_variant 1 NM_001005242.3 ENSP00000342800 P1Q99959-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1457808
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
725060
show subpopulations
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:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024This sequence change affects an acceptor splice site in intron 2 of the PKP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 23671136, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 188654). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 31, 2019The c.337-2A>T variant in PKP2 has been reported in 3 individual with ARVD/C (Bhonsale 2013, Walsh 2017) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 188654). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in individuals with arrhythmogenic right ventricular cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, the c.337-2A>T variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 05, 2022Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31775751, 32372669, 23871885, 27532257, 23671136, 32123317, 31402444, 31386562, 33087929, 25820315) -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 09, 2023The c.337-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 3 in the PKP2 gene. This alteration has been previously reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Bhonsale A, Circ Arrhythm Electrophysiol 2013 Jun; 6(3):569-78). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 13, 2024Variant summary: PKP2 c.337-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.337-2A>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31386562, 23671136, 26314686). ClinVar contains an entry for this variant (Variation ID: 188654). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
33
DANN
Uncertain
0.98
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
D;D
GERP RS
4.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.82
Position offset: -27
DS_AL_spliceai
0.99
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786204389; hg19: chr12-33031479; API