rs139851304

chr12-32877868-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005242.3(PKP2):c.1012A>G(p.Thr338Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,784 control chromosomes in the GnomAD database, including 26 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T338I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (21 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: -2.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024301708).
• BP6: Variant 12-32877868-T-C is Benign according to our data. Variant chr12-32877868-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 45003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32877868-T-C is described in Lovd as [Benign]. Variant chr12-32877868-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00149 (227/152354) while in subpopulation SAS AF= 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 5 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1012A>G	p.Thr338Ala	missense_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1012A>G	p.Thr338Ala	missense_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152236 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00222 AC: 553 AN: 249154 Hom.: 5 AF XY: 0.00216 AC XY: 291 AN XY: 134888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.0358

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000950

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00131 AC: 1916 AN: 1461430 Hom.: 21 Cov.: 32 AF XY: 0.00130 AC XY: 948 AN XY: 727034

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000421

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152354 Hom.: 5 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74506

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00259 Hom.: 10

Bravo AF: 0.00161

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	p.Thr338Ala in exon 3 of PKP2: This variant is not expected to have clinical sig nificance due its presence in the general population and a lack of evolutionary conservation (multiple mammals carry an alanine (Ala) at this position despite h igh nearby amino acid conservation). This variant has also been identified in 0. 3% (192/65422) of European chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs139851304). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 20, 2019	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Arrhythmogenic right ventricular dysplasia 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 10, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PKP2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	This variant is associated with the following publications: (PMID: 25196244, 20864495, 20031616, 26310507, 28255936) -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 01, 2014

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 10, 2015

- -

PKP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2017

This alteration is classified as 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	0.060
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.0010
Dann	Benign	0.87
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.20
Sift	Benign	0.44	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;B
Vest4		0.021
MVP		0.49
MPC		0.15
ClinPred		0.0062	T
GERP RS		-8.1
Varity_R		0.039
gMVP		0.33

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: rs139851304; hg19: chr12-33030802;