rs1046116

Variant names:

• chr12-32869000-A-G
• rs1046116
• NM_001005242.3:c.1097T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005242.3(PKP2):​c.1097T>C​(p.Leu366Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,432 control chromosomes in the GnomAD database, including 38,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3000 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35883 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.97
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008521527).
• BP6: Variant 12-32869000-A-G is Benign according to our data. Variant chr12-32869000-A-G is described in ClinVar as Benign. ClinVar VariationId is 45006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 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.1097T>C	p.Leu366Pro	missense	Exon 4 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1097T>C	p.Leu366Pro	missense	Exon 4 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.1097T>C	p.Leu366Pro	missense	Exon 4 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.1097T>C	p.Leu366Pro	missense	Exon 4 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.1097T>C	p.Leu366Pro	missense	Exon 4 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.1097T>C	p.Leu366Pro	missense	Exon 4 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30093 AN: 152040 Hom.: 2999 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.180 AC: 45239 AN: 251308 AF XY: 0.182

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0294

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.216 AC: 316176 AN: 1461272 Hom.: 35883 Cov.: 33 AF XY: 0.215 AC XY: 156088 AN XY: 726994

African (AFR) AF: 0.201 AC: 6728 AN: 33472

American (AMR) AF: 0.133 AC: 5954 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4487 AN: 26136

East Asian (EAS) AF: 0.0277 AC: 1098 AN: 39696

South Asian (SAS) AF: 0.165 AC: 14265 AN: 86242

European-Finnish (FIN) AF: 0.193 AC: 10266 AN: 53308

Middle Eastern (MID) AF: 0.237 AC: 1362 AN: 5736

European-Non Finnish (NFE) AF: 0.233 AC: 259444 AN: 1111584

Other (OTH) AF: 0.208 AC: 12572 AN: 60376

GnomAD4 genome AF: 0.198 AC: 30112 AN: 152160 Hom.: 3000 Cov.: 32 AF XY: 0.195 AC XY: 14492 AN XY: 74398

African (AFR) AF: 0.195 AC: 8099 AN: 41496

American (AMR) AF: 0.166 AC: 2538 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3468

East Asian (EAS) AF: 0.0328 AC: 170 AN: 5184

South Asian (SAS) AF: 0.155 AC: 747 AN: 4830

European-Finnish (FIN) AF: 0.198 AC: 2102 AN: 10596

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15215 AN: 67994

Other (OTH) AF: 0.193 AC: 407 AN: 2110

Alfa AF: 0.211 Hom.: 14879

Bravo AF: 0.196

TwinsUK AF: 0.230 AC: 852

ALSPAC AF: 0.226 AC: 870

ESP6500AA AF: 0.200 AC: 883

ESP6500EA AF: 0.230 AC: 1979

ExAC AF: 0.180 AC: 21856

Asia WGS AF: 0.111 AC: 384 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Arrhythmogenic right ventricular dysplasia 9 (6)
-	-	6	not specified (6)
-	-	3	Cardiomyopathy (3)
-	-	2	Arrhythmogenic right ventricular cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.4
DANN	Benign	0.24
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.13
Sift	Benign	0.41	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.25
ClinPred		0.0021	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.33
Mutation Taster		=99/1	polymorphism (auto)

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: rs1046116; hg19: chr12-33021934; COSMIC: COSV107228382;