rs149930872

Positions:

• chr12-32843224-G-A
• chr12-32843224-G-T

Variant summary

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

The ENST00000070846.11(PKP2):​c.1468C>T​(p.Arg490Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 711,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R490Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: PKP2 ENST00000070846.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:11
• Conservation: PhyloP100: -1.35

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=0.015172392).
• BP6: Variant 12-32843224-G-A is Benign according to our data. Variant chr12-32843224-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179026.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=6, Benign=1}. Variant chr12-32843224-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000507 (77/151962) while in subpopulation SAS AF= 0.00104 (5/4806). AF 95% confidence interval is 0.000791. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1379-2019C>T		intron_variant		ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1379-2019C>T		intron_variant		1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000422 AC: 97 AN: 230084 Hom.: 0 AF XY: 0.000438 AC XY: 55 AN XY: 125432

Gnomad AFR exome AF: 0.000857

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000929

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.000420 AC: 235 AN: 559126 Hom.: 1 Cov.: 8 AF XY: 0.000460 AC XY: 139 AN XY: 302148

Gnomad4 AFR exome AF: 0.000790

Gnomad4 AMR exome AF: 0.000443

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000840

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.000440

GnomAD4 genome AF: 0.000507 AC: 77 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74274

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000506 Hom.: 0

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000462 AC: 56

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2022	Variant summary: PKP2 c.1468C>T (p.Arg490Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools (Alamut) predict no significant impact on normal splicing, which was confirmed by Gandjbakhch_2011 using transcriptional analysis in heart tissue. The variant allele was found at a frequency of 0.00042 in 231024 control chromosomes, predominantly at a frequency of 0.00093 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 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1468C>T has been reported in the literature in individuals affected with arrhythmogenic right ventricular cardiomyopathy, sudden unexplained death and cardiac disease (Gandjbakhch_2011, Sanchez_2016, Iglesia_2021). Additionally, one publication reported three siblings, including two reported as affected/possibly affected ARVC and one reported as unaffected, and suggested this variant is not fully penetrant or does not segregate with disease. Moreover, another variant (DSP p.Glu2343Lys) was found in all three family members and may explain the phenotype in these patients (Gandjbakhch_2011). Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign/benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 04, 2013	Arg490Trp in exon 6 of PKP2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , orangutan, rhesus macaque, baboon, and marmoset have a tryptophan (Trp) at thi s position despite high nearby amino acid conservation. Addtionally, functional studies have shown that this variant does not impact splicing (Gandjbankhch 201 1). It has also been identified in 0.15% (7/4402) of African American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs149930872). Arg490Trp in exon 6 of PKP2 (rs149930872; allele frequency = 0 .15%, 7/4402) ** -

Cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Oct 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 18, 2018	- -

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PKP2: BP4 -

Becker muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Dilated cardiomyopathy 3B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

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	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.47
DANN	Benign	0.77
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.00079	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.053
Sift	Benign	0.061	T
Sift4G	Benign	0.11	T
Polyphen		0.90	P
Vest4		0.21
MVP		0.46
MPC		0.16
ClinPred		0.0021	T
GERP RS		-1.0
Varity_R		0.057
gMVP		0.30

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: rs149930872; hg19: chr12-32996158;