NM_001005242.3:c.148_151delACAG

Variant names:

• chr12-32896580-ACTGT-A
• rs397516997
• NM_001005242.3:c.148_151delACAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 20P and 4B. PVS1 PS3 PP5_Very_Strong BS2

The NM_001005242.3(PKP2):​c.148_151delACAG​(p.Thr50SerfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000321 in 1,589,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000061833: An in vitro functional study using human induced pluripotent stem cell derived cardiomyocytes from an ARVC patient with the variant provide some evidence that this variant impacts protein function by disrupting desmosomal function and morphology and potentially recapitulating the ARVC phenotype in the culture dish (Caspi 2013 PMID:24200905)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T50T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 0.813
• 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

ENSG00000309487 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000061833: An in vitro functional study using human induced pluripotent stem cell derived cardiomyocytes from an ARVC patient with the variant provide some evidence that this variant impacts protein function by disrupting desmosomal function and morphology and potentially recapitulating the ARVC phenotype in the culture dish (Caspi 2013 PMID: 24200905).; SCV000236277: Functional studies have demonstrated that this variant results in reduced PKP2 mRNA and protein levels (Caspi et al., 2013);; SCV003925212: Functional studies have demonstrated that this variant results in reduced PKP2mRNA and protein levels [PMID: 24200905].
• PP5: Variant 12-32896580-ACTGT-A is Pathogenic according to our data. Variant chr12-32896580-ACTGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 45028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 47 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.148_151delACAG	p.Thr50SerfsTer61	frameshift	Exon 1 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.148_151delACAG	p.Thr50SerfsTer61	frameshift	Exon 1 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.148_151delACAG	p.Thr50SerfsTer61	frameshift	Exon 1 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.148_151delACAG	p.Thr50SerfsTer61	frameshift	Exon 1 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.148_151delACAG	p.Thr50SerfsTer61	frameshift	Exon 1 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.148_151delACAG	p.Thr50SerfsTer61	frameshift	Exon 1 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000327 AC: 47 AN: 1437558 Hom.: 0 AF XY: 0.0000294 AC XY: 21 AN XY: 715218

African (AFR) AF: 0.0000306 AC: 1 AN: 32670

American (AMR) AF: 0.00 AC: 0 AN: 44048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.0000768 AC: 3 AN: 39070

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.0000352 AC: 39 AN: 1108666

Other (OTH) AF: 0.00 AC: 0 AN: 59708

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152062 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Arrhythmogenic right ventricular dysplasia 9 (11)
8	-	-	not provided (8)
4	-	-	Arrhythmogenic right ventricular cardiomyopathy (4)
2	-	-	Cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial isolated arrhythmogenic right ventricular dysplasia (1)
1	-	-	PKP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs397516997; hg19: chr12-33049514;