rs397516993

Variant names:

• chr12-32850771-ATTTG-A
• rs397516993
• NM_001005242.3:c.1369_1372delCAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004572.4(PKP2):​c.1369_1372delCAAA​(p.Gln457fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PKP2 NM_004572.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.42
• Publications: 2 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: Pathogenic. The variant received 18 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 12-32850771-ATTTG-A is Pathogenic according to our data. Variant chr12-32850771-ATTTG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1369_1372delCAAA	p.Gln457fs	frameshift	Exon 5 of 13	NP_001005242.2
	PKP2	NM_004572.4		c.1369_1372delCAAA	p.Gln457fs	frameshift	Exon 5 of 14	NP_004563.2
	PKP2	NM_001407155.1		c.1369_1372delCAAA	p.Gln457fs	frameshift	Exon 5 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.1369_1372delCAAA	p.Gln457fs	frameshift	Exon 5 of 13	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.1369_1372delCAAA	p.Gln457fs	frameshift	Exon 5 of 14	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.1369_1372delCAAA	p.Gln457fs	frameshift	Exon 5 of 12	ENSP00000515065.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459426 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726104

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4514

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111148

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Arrhythmogenic right ventricular cardiomyopathy (2)
1	-	-	Arrhythmogenic right ventricular dysplasia 9 (1)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial isolated arrhythmogenic right ventricular dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs397516993; hg19: chr12-33003705;