12-32796167-G-T

Variant names:

• chr12-32796167-G-T
• rs139734328
• NM_001005242.3:c.2299C>A

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.2299C>A​(p.Arg767Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000855 in 1,614,042 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts 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. R767H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (7 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19
• Conservation: PhyloP100: 3.69
• Publications: 22 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=0.020314664).
• BP6: Variant 12-32796167-G-T is Benign according to our data. Variant chr12-32796167-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45068.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000749 (114/152206) while in subpopulation AMR AF = 0.000851 (13/15282). AF 95% confidence interval is 0.000664. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 114 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.2299C>A	p.Arg767Ser	missense	Exon 11 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.2431C>A	p.Arg811Ser	missense	Exon 12 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407156.1		c.2134C>A	p.Arg712Ser	missense	Exon 10 of 12	NP_001394085.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.2299C>A	p.Arg767Ser	missense	Exon 11 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.2431C>A	p.Arg811Ser	missense	Exon 12 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000549461.3	TSL:2	c.442C>A	p.Arg148Ser	missense	Exon 3 of 5	ENSP00000519092.1	A0AAQ5BGX6

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152088 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000907 AC: 228 AN: 251482 AF XY: 0.00101

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000866 AC: 1266 AN: 1461836 Hom.: 7 Cov.: 34 AF XY: 0.000920 AC XY: 669 AN XY: 727226

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00880 AC: 230 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.000730 AC: 812 AN: 1111962

Other (OTH) AF: 0.00136 AC: 82 AN: 60394

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74402

African (AFR) AF: 0.000120 AC: 5 AN: 41526

American (AMR) AF: 0.000851 AC: 13 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Arrhythmogenic right ventricular dysplasia 9 (6)
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Arrhythmogenic right ventricular cardiomyopathy (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Familial isolated arrhythmogenic right ventricular dysplasia (1)
-	1	-	Long QT syndrome (1)
-	-	1	PKP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.024	D
Polyphen		0.27	B
Vest4		0.81
MVP		0.73
MPC		0.54
ClinPred		0.088	T
GERP RS		5.1
Varity_R		0.34
gMVP		0.59
Mutation Taster		=78/22	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: rs139734328; hg19: chr12-32949101; COSMIC: COSV50756535; COSMIC: COSV50756535;