rs144601090

Positions:

• chr12-32821439-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

The NM_001005242.3(PKP2):​c.1930T>C​(p.Ser644Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S644F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:12
• Conservation: PhyloP100: 7.97

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 Likely_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• PP5: Variant 12-32821439-A-G is Pathogenic according to our data. Variant chr12-32821439-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45055.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=10, Likely_pathogenic=3}. Variant chr12-32821439-A-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1930T>C	p.Ser644Pro	missense_variant	9/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1930T>C	p.Ser644Pro	missense_variant	9/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000478

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251382 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.000246

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727234

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74434

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0000654

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: 0.000473

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2021	The p.Ser688Pro variant in PKP2 has been reported in 5 individuals with ARVC (van Tintelen 2006 PMID: 16567567, Quarta 2011 PMID: 21606390, and Zhang 2012 PMID: 22019812, Walsh 2017 PMID: 27532257, DeWitt 2019 PMID: 31319917, van Lint 2019 PMID: 31386562), in 1 individual with sudden unexplained death in the young (SUDY) (Shanks 2018 PMID: 29915097) and identified by our laboratory in 1 individual with DCM and ARVC and 2 individuals with ARVC. It has also been identified in 0.044% (11/24964) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 24, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces serine with proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 688 of the PKP2 protein (p.Ser688Pro). This variant is present in population databases (rs144601090, gnomAD 0.05%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 21606390, 22019812, 27532257, 31319917, 32522011; Invitae). ClinVar contains an entry for this variant (Variation ID: 45055). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	Reported in association with ARVC and sudden unexplained death, however, specific clinical information or segregation data were not provided (van Tintelen et al., 2006; Cox et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Zhang et al., 2012; Shanks et al., 2018); Reported in a child with acute myocarditis who was compound heterozygous for a paternally inherited S688P variant and a maternally inherited D829N variant; all family members were reported as unaffected (Belkaya et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 45055; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21606396, 31386562, 21636032, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 28359509, 29915097, 23871674, 31402444, 32522011, 33232181) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 30, 2022	PP3 -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2023	This missense variant replaces serine with proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

The p.S688P variant (also known as c.2062T>C), located in coding exon 10 of the PKP2 gene, results from a T to C substitution at nucleotide position 2062. The serine at codon 688 is replaced by proline, an amino acid with similar properties. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Zhang M et al. Circ. J., 2012 Oct;76:189-94; DeWitt ES et al. J Am Coll Cardiol, 2019 07;74:346-358; Goudal A et al. Hum Mutat, 2022 Sep;43:1333-1342; Olivetti NQS et al. Circ Arrhythm Electrophysiol, 2023 Feb;16:e011391). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Shanks GW et al. Circulation, 2018 06;137:2705-2715). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.94
MVP		0.93
MPC		0.75
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144601090; hg19: chr12-32974373;