rs551045165

chr12-32796233-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):c.2233A>G(p.Ile745Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,611,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. I745N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 1.51

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007276565).
• BP6: Variant 12-32796233-T-C is Benign according to our data. Variant chr12-32796233-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179097.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr12-32796233-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000858 (13/151504) while in subpopulation SAS AF= 0.00166 (8/4810). AF 95% confidence interval is 0.000827. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2233A>G	p.Ile745Val	missense_variant	11/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2233A>G	p.Ile745Val	missense_variant	11/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000858 AC: 13 AN: 151504 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251432 Hom.: 0 AF XY: 0.000500 AC XY: 68 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1460040 Hom.: 0 Cov.: 33 AF XY: 0.000315 AC XY: 229 AN XY: 726404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00274

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.0000858 AC: 13 AN: 151504 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73886

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.0000814 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2013	Variant classified as Uncertain Significance - Favor Benign. The Ile789Val varia nt in PKP2 has not been reported in individuals with cardiomyopathy or in large population studies. Isoleucine (Ile) at position 789 is not conserved in mammals or evolutionarily distant species and 1 species (bushbaby) carries a valine (Va l; this variant), raising the possibility that this change may be tolerated. Add itional computational analyses (biochemical amino acid properties, AlignGVGD, Po lyPhen2, and SIFT) also suggest that this variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. Althou gh this data supports that the Ile789Val variant may be benign, additional studi es are needed to fully assess its clinical significance. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 26, 2018	Variant summary: PKP2 c.2365A>G (p.Ile789Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 276984 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Cardiomyopathy phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism. c.2365A>G has been reported in the literature in an individual affected with Cardiomyopathy, however this individual also carried another likely pathogenic MYH7 variant, c.1063G>A (p.Ala355Thr)that could explain his phenotype (Ceyhan-Birsoy 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant twice as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	This variant is associated with the following publications: (PMID: 27066507, 25819062, 27535533) -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

Jul 03, 2019

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 26, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	9.6
Dann	Benign	0.85
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.027
Sift	Benign	0.33	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0020	B;B
Vest4		0.21
MVP		0.32
MPC		0.13
ClinPred		0.017	T
GERP RS		2.7
Varity_R		0.017
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs551045165; hg19: chr12-32949167;