12-32868925-A-T

Variant names:

• chr12-32868925-A-T
• rs397516987
• NM_001005242.3:c.1170+2T>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.1170+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: PKP2 NM_001005242.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.93
• Publications: 2 publications found

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]

PKP2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32868925-A-T is Pathogenic according to our data. Variant chr12-32868925-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1170+2T>A		splice_donor_variant, intron_variant	Intron 4 of 12	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1170+2T>A		splice_donor_variant, intron_variant	Intron 4 of 12	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 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, 17041889, 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 or hypertrophic cardiomyopathy (PMID: 20400443, 25611685, 32372669; internal data). ClinVar contains an entry for this variant (Variation ID: 45011). 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

Feb 20, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 1170+2T>A variant in PKP2 has not been reported in the literature, but has b een identified by our laboratory in 1 individual with ARVC and segregated with d isease in 1 affected relative (LMM unpublished data). This variant has also not been identified in large European American and African American populations by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which incr eases the likelihood that it is pathogenic. However, we cannot exclude that it m ay be common in other populations. This variant occurs in the invariant region ( +/- 1,2) of the splice consensus sequence and is predicted to cause altered spli cing leading to an abnormal or absent protein. In summary, this variant is likel y to be pathogenic, though additional studies are required to fully establish it s clinical significance.

not provided Pathogenic:1

Jun 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with ARVC in published literature and by another clinical laboratory in ClinVar, and segregated with disease in at least one relative (ClinVar SCV000061816.6; ClinVar; Smith et al., 2020); Identified in a 53-year-old individual with hypertrophic cardiomyopathy in published literature (Alfares et al., 2015); however, a pathogenic variant in the MYH7 gene was also identified, and further details regarding follow-up cardiac investigations and segregation studies were not available.; Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 32372669, 25611685)

Cardiovascular phenotype Pathogenic:1

Nov 05, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1170+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 4 in the PKP2 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Another alteration impacting the same donor site (c.1170+1G>A) has been described in a patient with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800). 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		3.9
PROVEAN	Benign	0.0	.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.0
GERP RS		4.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs397516987; hg19: chr12-33021859;