rs146708884

Variant names:

• chr12-32896558-C-A
• rs146708884
• NM_001005242.3:c.174G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-32896558-C-A
• chr12-32896558-C-T
• chr12-32896558-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005242.3(PKP2):​c.174G>T​(p.Glu58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,589,246 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E58G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (56 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.66
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050928295).
• BP6: Variant 12-32896558-C-A is Benign according to our data. Variant chr12-32896558-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00652 (993/152286) while in subpopulation NFE AF = 0.00375 (255/68024). AF 95% confidence interval is 0.00337. There are 31 homozygotes in GnomAd4. There are 697 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 993 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.174G>T	p.Glu58Asp	missense	Exon 1 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.174G>T	p.Glu58Asp	missense	Exon 1 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.174G>T	p.Glu58Asp	missense	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.174G>T	p.Glu58Asp	missense	Exon 1 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.174G>T	p.Glu58Asp	missense	Exon 1 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.174G>T	p.Glu58Asp	missense	Exon 1 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 152168 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00549 AC: 1187 AN: 216324 AF XY: 0.00587

Gnomad AFR exome AF: 0.000792

Gnomad AMR exome AF: 0.000882

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00451 AC: 6480 AN: 1436960 Hom.: 56 Cov.: 32 AF XY: 0.00439 AC XY: 3136 AN XY: 714878

African (AFR) AF: 0.000462 AC: 15 AN: 32488

American (AMR) AF: 0.00111 AC: 49 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 45 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 38960

South Asian (SAS) AF: 0.00175 AC: 148 AN: 84756

European-Finnish (FIN) AF: 0.0407 AC: 1579 AN: 38834

Middle Eastern (MID) AF: 0.000883 AC: 4 AN: 4528

European-Non Finnish (NFE) AF: 0.00399 AC: 4425 AN: 1107730

Other (OTH) AF: 0.00360 AC: 215 AN: 59736

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152286 Hom.: 31 Cov.: 33 AF XY: 0.00936 AC XY: 697 AN XY: 74440

African (AFR) AF: 0.000722 AC: 30 AN: 41580

American (AMR) AF: 0.00111 AC: 17 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.0627 AC: 666 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00375 AC: 255 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00312 Hom.: 5

Bravo AF: 0.00203

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00287 AC: 24

ExAC AF: 0.00632 AC: 753

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	3	Arrhythmogenic right ventricular dysplasia 9 (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.024	D
Polyphen		0.63	P
Vest4		0.33
MutPred		0.20		Gain of phosphorylation at S53 (P = 0.187)
MVP		0.84
MPC		0.22
ClinPred		0.011	T
GERP RS		2.0
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.21
gMVP		0.28
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146708884; hg19: chr12-33049492;