rs146882581

Variant names:

• chr12-32841139-G-A
• rs146882581
• NM_001005242.3:c.1445C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.1445C>T​(p.Thr482Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,778 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. T482A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: 0.694
• Publications: 18 publications found

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]

PKP2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022124588).
• BP6: Variant 12-32841139-G-A is Benign according to our data. Variant chr12-32841139-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45033.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00387 (589/152288) while in subpopulation AMR AF = 0.0114 (174/15292). AF 95% confidence interval is 0.01. There are 3 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 589 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.1445C>T	p.Thr482Met	missense	Exon 6 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1577C>T	p.Thr526Met	missense	Exon 7 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.1445C>T	p.Thr482Met	missense	Exon 6 of 12	NP_001394084.1	A0A8V8TPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1445C>T	p.Thr482Met	missense	Exon 6 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.1577C>T	p.Thr526Met	missense	Exon 7 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.1445C>T	p.Thr482Met	missense	Exon 6 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 590 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00245 AC: 617 AN: 251334 AF XY: 0.00225

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00572

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00263 AC: 3845 AN: 1460490 Hom.: 7 Cov.: 30 AF XY: 0.00258 AC XY: 1876 AN XY: 726700

African (AFR) AF: 0.00508 AC: 170 AN: 33448

American (AMR) AF: 0.00530 AC: 237 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53402

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00290 AC: 3222 AN: 1110766

Other (OTH) AF: 0.00303 AC: 183 AN: 60342

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74450

African (AFR) AF: 0.00520 AC: 216 AN: 41576

American (AMR) AF: 0.0114 AC: 174 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 68030

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00303 Hom.: 3

Bravo AF: 0.00430

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00230 AC: 279

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Arrhythmogenic right ventricular dysplasia 9 (6)
-	1	1	Arrhythmogenic right ventricular cardiomyopathy (2)
-	-	2	Cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial isolated arrhythmogenic right ventricular dysplasia (1)
-	-	1	Long QT syndrome (1)
-	-	1	Premature ventricular contraction;C1142166:Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.7
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.69
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.070	T
Sift4G	Benign	0.070	T
Polyphen		0.051	B
Vest4		0.53
MVP		0.83
MPC		0.18
ClinPred		0.0030	T
GERP RS		2.0
Varity_R		0.076
gMVP		0.30
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs146882581; hg19: chr12-32994073; COSMIC: COSV50726327;