NM_001005242.3:c.2357+13_2357+14insC

Variant names:

• chr12-32796095-A-AG
• rs149968852
• NM_001005242.3:c.2357+13_2357+14insC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001005242.3(PKP2):​c.2357+13_2357+14insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,609,152 control chromosomes in the GnomAD database, including 30,631 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3884 hom., cov: 27)
  • Exomes 𝑓: 0.17 (26747 hom.)
• Consequence: PKP2 NM_001005242.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.980
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-32796095-A-AG is Benign according to our data. Variant chr12-32796095-A-AG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

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.2357+13_2357+14insC		intron	N/A	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.2489+13_2489+14insC		intron	N/A	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.2168-3365_2168-3364insC		intron	N/A	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.2357+13_2357+14insC		intron	N/A	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.2489+13_2489+14insC		intron	N/A	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.2168-3365_2168-3364insC		intron	N/A	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31239 AN: 151936 Hom.: 3877 Cov.: 27

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.211 AC: 52961 AN: 251360 AF XY: 0.212

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.554

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.170 AC: 247999 AN: 1457096 Hom.: 26747 Cov.: 33 AF XY: 0.174 AC XY: 125923 AN XY: 725198

African (AFR) AF: 0.283 AC: 9442 AN: 33368

American (AMR) AF: 0.168 AC: 7526 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4033 AN: 26092

East Asian (EAS) AF: 0.567 AC: 22478 AN: 39644

South Asian (SAS) AF: 0.324 AC: 27876 AN: 86104

European-Finnish (FIN) AF: 0.171 AC: 9139 AN: 53416

Middle Eastern (MID) AF: 0.148 AC: 849 AN: 5734

European-Non Finnish (NFE) AF: 0.140 AC: 155405 AN: 1107786

Other (OTH) AF: 0.187 AC: 11251 AN: 60234

GnomAD4 genome AF: 0.206 AC: 31248 AN: 152056 Hom.: 3884 Cov.: 27 AF XY: 0.212 AC XY: 15744 AN XY: 74288

African (AFR) AF: 0.281 AC: 11647 AN: 41488

American (AMR) AF: 0.179 AC: 2737 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 551 AN: 3464

East Asian (EAS) AF: 0.566 AC: 2898 AN: 5120

South Asian (SAS) AF: 0.330 AC: 1585 AN: 4810

European-Finnish (FIN) AF: 0.182 AC: 1926 AN: 10576

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.137 AC: 9345 AN: 68004

Other (OTH) AF: 0.183 AC: 386 AN: 2110

Alfa AF: 0.156 Hom.: 491

Bravo AF: 0.206

Asia WGS AF: 0.418 AC: 1450 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Arrhythmogenic right ventricular dysplasia 9 (3)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98
Mutation Taster		=25/75	disease causing

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: rs149968852; hg19: chr12-32949029;