chr12-32843247-CTGGGA-C

Variant names:

• chr12-32843247-CTGGGA-C
• rs775995156
• ENST00000070846.11:c.1440_1444delTCCCA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004572.4(PKP2):​c.1440_1444delTCCCA​(p.Asn480LysfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKP2 NM_004572.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:5
• Conservation: PhyloP100: 0.544
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32843247-CTGGGA-C is Pathogenic according to our data. Variant chr12-32843247-CTGGGA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419977.

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.1379-2047_1379-2043delTCCCA		intron	N/A	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1440_1444delTCCCA	p.Asn480LysfsTer20	frameshift	Exon 6 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407157.1		c.1440_1444delTCCCA	p.Asn480LysfsTer20	frameshift	Exon 6 of 10	NP_001394086.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000070846.11	TSL:1	c.1440_1444delTCCCA	p.Asn480LysfsTer20	frameshift	Exon 6 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1379-2047_1379-2043delTCCCA		intron	N/A	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000700559.2		c.1379-2047_1379-2043delTCCCA		intron	N/A	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000833 AC: 2 AN: 239996 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000449 AC: 4 AN: 891198 Hom.: 0 AF XY: 0.00000876 AC XY: 4 AN XY: 456664

African (AFR) AF: 0.00 AC: 0 AN: 20056

American (AMR) AF: 0.00 AC: 0 AN: 36910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14998

East Asian (EAS) AF: 0.00 AC: 0 AN: 15330

South Asian (SAS) AF: 0.00 AC: 0 AN: 76830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3882

European-Non Finnish (NFE) AF: 0.00000451 AC: 3 AN: 665104

Other (OTH) AF: 0.0000299 AC: 1 AN: 33484

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775995156; hg19: chr12-32996181;