12-32802402-C-T

Variant names:

• chr12-32802402-C-T
• rs794729116
• NM_001005242.3:c.2167+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.2167+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000041 in 1,461,714 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: 0.0000041 (0 hom.)
• 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:7
• Conservation: PhyloP100: 5.44

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 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 12-32802402-C-T is Pathogenic according to our data. Variant chr12-32802402-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202005.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.2167+1G>A		splice_donor_variant, intron_variant	Intron 10 of 12	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.2167+1G>A		splice_donor_variant, intron_variant	Intron 10 of 12	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727168

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Apr 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in at least two patients with cardiac arrest and/or referred to an inherited arrhythmia clinic (PMID: 26743238, 36138163). The PKP2 c.2299+1G>A variant co-occurred with a pathogenic DSG2 variant in one proband and with a MYH11 variant of uncertain significance in another proband, and it was observed in several asymptomatic family members (PMID: 36138163). The PKP2 c.2299+1G>A variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Jun 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2299+1G>A variant in PKP2 has not been previously reported in individuals with cardiomyopathy or in large population studies, but has been reported in ClinVar (Variation ID: 202005). 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. Splicing variants and other truncating variants in PKP2 are an established disease mechanism in ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.2299+1G>A variant is likely pathogenic. -

not provided Pathogenic:2

May 01, 2012

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2299+1 G>A: IVS11+1 G>A in intron 11 of the PKP2 gene (NM_004572.3). The c.2299+1 G>A mutation in the PKP2 gene has also not been reported previously as a disease-causing mutation, however this mutation destroys the consensus splice donor site of intron 11 and is expected to cause abnormal gene splicing. Three splice prediction algorithms concur that c.2299+1 G>A results in the loss of the normal splice donor site. This mutation is predicted to lead to either an abnormal message, which is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, other splice site mutations (c.2489+1 G>A, c.2489+4 C>A) in the PKP2 gene have been reported in association with ARVC (Van der Zwaag P et al., 2009). Therefore, c.2299+1 G>A in the PKP2 gene is interpreted to be a disease-causing mutation. The variant is found in ARVC panel(s). -

Dec 22, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Nov 11, 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 11 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 (PMID: 26743238, 36138163). ClinVar contains an entry for this variant (Variation ID: 202005). 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. -

Cardiomyopathy Pathogenic:1

May 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 11 of the PKP2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in a few individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238, 36138163). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jul 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2299+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 11 of the PKP2 gene. This variant was reported in individuals with features consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, details were limited (Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs794729116; hg19: chr12-32955336;