chr12-32796206-T-C

Variant names:

• chr12-32796206-T-C
• rs112592855
• NM_001005242.3:c.2260A>G

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.2260A>G​(p.Thr754Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,816 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. T754R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 1.67
• Publications: 10 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=0.011504084).
• BP6: Variant 12-32796206-T-C is Benign according to our data. Variant chr12-32796206-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45067.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00216 (328/152024) while in subpopulation AFR AF = 0.0076 (315/41440). AF 95% confidence interval is 0.00691. There are 1 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 328 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.2260A>G	p.Thr754Ala	missense	Exon 11 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.2392A>G	p.Thr798Ala	missense	Exon 12 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407156.1		c.2095A>G	p.Thr699Ala	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.2260A>G	p.Thr754Ala	missense	Exon 11 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.2392A>G	p.Thr798Ala	missense	Exon 12 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000549461.3	TSL:2	c.403A>G	p.Thr135Ala	missense	Exon 3 of 5	ENSP00000519092.1	A0AAQ5BGX6

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 326 AN: 151906 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000636 AC: 160 AN: 251470 AF XY: 0.000508

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000271 AC: 396 AN: 1461792 Hom.: 3 Cov.: 34 AF XY: 0.000242 AC XY: 176 AN XY: 727208

African (AFR) AF: 0.00801 AC: 268 AN: 33474

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111920

Other (OTH) AF: 0.000414 AC: 25 AN: 60392

GnomAD4 genome AF: 0.00216 AC: 328 AN: 152024 Hom.: 1 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74276

African (AFR) AF: 0.00760 AC: 315 AN: 41440

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67998

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000621 Hom.: 0

Bravo AF: 0.00247

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.15
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.54
MVP		0.64
MPC		0.16
ClinPred		0.027	T
GERP RS		5.1
Varity_R		0.064
gMVP		0.37
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs112592855; hg19: chr12-32949140;