rs786204387

Variant names:

• chr12-32879035-G-C
• rs786204387
• NM_001005242.3:c.224-3C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32879035-G-C
• chr12-32879035-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001005242.3(PKP2):​c.224-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 1,273,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: PKP2 NM_001005242.3 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.74

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.224-3C>G		splice_region_variant, intron_variant	Intron 1 of 12	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.224-3C>G		splice_region_variant, intron_variant	Intron 1 of 12	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000236 AC: 3 AN: 1273286 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 643356

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: 0.00000318

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:2

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of PKP2-related conditions (PMID: 23671136, 24125834, 30830208). ClinVar contains an entry for this variant (Variation ID: 188652). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKP2 NM_004572.3 exon 2 c.224-3C>G: This variant has been reported in the literature in at least two individuals with ARVC (Bhonsale 2013 PMID:23671136, Bao 2013 PMID:24125834). This variant is not present in large control databases but is present in ClinVar (Variation ID:188652). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Uncertain:1

Jun 11, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS1-3 C>G (c.224-3 C>G) in PKP2 (NM_004572.3) Based on the fact that all the known cases are Chinese and we lack a large general population dataset on Asians, we classify the variant as of uncertain significance, probably disease causing. More ancestry-matched control data would be helpful in assessing pathogenicity. In total the variant has been seen in at least 2, possibly 3 unrelated cases of ARVC, all Chinese (not including the patient's case). We have seen the variant in one other individual with ARVC in our clinic. That individual also happens to be of Chinese ancestry. In the other family with ARVC we are for with this variant it was also present in the paternal first cousin with ARVC. Bao et al (2013) observed the variant in 1 of 90 unrelated individuals with ARVC in their Chinese cohort who underwent analysis of 9 genes associated with ARVC. The GeneDx report also notes it was included in a paper from the Hopkins registry, however that case is almost certainly the patient, since she is enrolled in their registry (Bhonsale et al 2013). It is not listed in ClinVar (as of October 15th, 2014). I found a 2011 abstract online from a Chinese group in Guangdong (none of the affiliations for the Bao et al group were in Guangdong). Unfortuantely it is in Chinese, but using google translate it appears they are reporting on an ARVC patient with this variant (http://www.cnki.net/KCMS/detail/detail.aspx?filename=ZGXZ201102011&dbname=cjfqtotal&dbcode=CJFQ&v=MDI5OTVrVUx6UFB5clRkTEc0SDlETXJZOUVaWVI2RGc4L3poWVU3enNPVDNpUXJSY3pGckNVUkw2ZlkrUnBGQ2o= and the paper - http://boyalunwen.com/up/thesis/20110617173315730.pdf). About 10% of published ARVC-associated variants are splicing variants in PKP2. Based on in silico analysis performed by GeneDx with three different programs that predict the impact of variants on splicing, this variant is expected to interfere with normal splicing. Another splicing variant affecting the same intron (IVS1+1G>A) has been reported in a patient with ARVC (Fressart et al 2010). In total this variant has not been seen in ~7527 controls or individuals from publicly available general population datasets, though only a minority of these match the patient's ancestry (360). IVS1-3C>G was absent in GeneDx’s 300 Caucasian and African-American controls. Unfortunately they have no Asian controls (matching the patient’s ancestry and the ancestry of the other cases). It was also not seen in a panel of 427 control individuals recently published by Kapplinger et al (2011). That included 127 individuals of asian ancestry. It is not listed in the 1000 genomes data (as of January 2nd, 2013). Specifically, the variant was not observed in low coverage (4-5x) sequencing of 60 Chinese individuals in that study (as of January 10th, 2012). Bao et al (2013) did not see it in 300 Chinese controls. In addition, it is not listed in dbSNP (as of January 2nd, 2012). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January 2nd, 2013). Note that this dataset does not match the patient's ancestry. LL _ also has TNNT2 VUS -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Feb 22, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C to G nucleotide substitution at the -3 position of intron 1 of the PKP2 gene. This variant is also known as IVS1-3C>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported in at least five unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23671136, 24125834, 25196244, 25820315, 30161220, 30830208, 36138163, 37418234). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). One of the affected probands has been reported to be compound heterozygous for this variant and c.2490-6T>C variant in the same gene (PMID: 30830208). The proband's heterozygous parents were unaffected with arrhythmogenic cardiomyopathy (PMID: 30830208). Based on the RNAseq analysis using the proband's explant heart sample, this study has reported that this c.224-3C>G variant causes skipping of exon 2, and c.2490-6T>C variant causes exon13 extension. Detailed molecular consequences of these variants were not described in this study but it was reported that the overall PKP2 protein expression in the proband's heart tissue was reduced (PMID: 30830208). The c.2490-6T>C variant is reported to be a benign variant (ClinVar variation ID: 414019). The available evidence is insufficient to determine the role of this c.224-3C>G variant in autosomal dominant aarrhythmogenic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Oct 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C to G nucleotide substitution at the -3 position of intron 1 of the PKP2 gene. This variant is also known as IVS1-3C>G in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported in at least five unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23671136, 24125834, 25196244, 25820315, 30161220, 30830208, 36138163, 37418234). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). One of the affected probands has been reported to be compound heterozygous for this variant and c.2490-6T>C variant in the same gene (PMID: 30830208). The proband's heterozygous parents were unaffected with arrhythmogenic cardiomyopathy (PMID: 30830208). Based on the RNAseq analysis using the proband's explant heart sample, this study has reported that this c.224-3C>G variant causes skipping of exon 2, and c.2490-6T>C variant causes exon13 extension. Detailed molecular consequences of these variants were not described in this study but it was reported that the overall PKP2 protein expression in the proband's heart tissue was reduced (PMID: 30830208). The c.2490-6T>C variant is reported to be a benign variant (ClinVar variation ID: 414019). The available evidence is insufficient to determine the role of this c.224-3C>G variant in autosomal dominant aarrhythmogenic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Jul 30, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 2 in the PKP2 gene. This variant has been reported in arrhythmogenic right ventricular dysplasia/cardiomyopathy cohorts, though two were the same study population (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Bhonsale A et al. Circ Arrhythm Electrophysiol, 2013 Jun;6:569-78; James CA et al. J. Am. Coll. Cardiol., 2013 Oct;62:1290-7). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.52		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204387; hg19: chr12-33031969;