12-32824092-C-T

Variant names:

• chr12-32824092-C-T
• rs146102241
• NM_001005242.3:c.1627G>A

Variant summary

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

The NM_004572.4(PKP2):​c.1759G>A​(p.Val587Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,611,974 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (17 hom.)
• Consequence: PKP2 NM_004572.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21
• Conservation: PhyloP100: 3.10
• Publications: 26 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: Labcorp Genetics (formerly Invitae), G2P
• 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=0.011907041).
• BP6: Variant 12-32824092-C-T is Benign according to our data. Variant chr12-32824092-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36681.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152282) while in subpopulation NFE AF = 0.00357 (243/68026). AF 95% confidence interval is 0.0032. There are 1 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 366 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004572.4. 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.1627G>A	p.Val543Ile	missense	Exon 7 of 13	NP_001005242.2
	PKP2	NM_004572.4		c.1759G>A	p.Val587Ile	missense	Exon 8 of 14	NP_004563.2
	PKP2	NM_001407155.1		c.1627G>A	p.Val543Ile	missense	Exon 7 of 12	NP_001394084.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1627G>A	p.Val543Ile	missense	Exon 7 of 13	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.1759G>A	p.Val587Ile	missense	Exon 8 of 14	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.1627G>A	p.Val543Ile	missense	Exon 7 of 12	ENSP00000515065.2

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00245 AC: 616 AN: 251180 AF XY: 0.00236

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00389 AC: 5685 AN: 1459692 Hom.: 17 Cov.: 29 AF XY: 0.00380 AC XY: 2762 AN XY: 726364

African (AFR) AF: 0.000778 AC: 26 AN: 33438

American (AMR) AF: 0.00268 AC: 120 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 282 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00449 AC: 4988 AN: 1110194

Other (OTH) AF: 0.00431 AC: 260 AN: 60322

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74454

African (AFR) AF: 0.00113 AC: 47 AN: 41540

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00382 Hom.: 0

Bravo AF: 0.00247

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00236 AC: 287

EpiCase AF: 0.00403

EpiControl AF: 0.00362

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	1	3	Arrhythmogenic right ventricular dysplasia 9 (4)
-	-	4	not provided (4)
-	1	2	Arrhythmogenic right ventricular cardiomyopathy (3)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	PKP2-related disorder (1)
-	-	1	Ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.31
MVP		0.71
MPC		0.60
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.51
Mutation Taster		=72/28	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: rs146102241; hg19: chr12-32977026;