rs537458442

Variant names:

• chr12-32843230-C-T
• rs537458442
• ENST00000070846.11:c.1462G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004572.4(PKP2):​c.1462G>A​(p.Gly488Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 790,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G488D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PKP2 NM_004572.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.454
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018732578).
• BP6: Variant 12-32843230-C-T is Benign according to our data. Variant chr12-32843230-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229142.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00021 (32/152284) while in subpopulation AFR AF = 0.000698 (29/41558). AF 95% confidence interval is 0.000498. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 32 AD gene.

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.1379-2025G>A		intron	N/A	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1462G>A	p.Gly488Ser	missense	Exon 6 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407157.1		c.1462G>A	p.Gly488Ser	missense	Exon 6 of 10	NP_001394086.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000070846.11	TSL:1	c.1462G>A	p.Gly488Ser	missense	Exon 6 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1379-2025G>A		intron	N/A	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000700559.2		c.1379-2025G>A		intron	N/A	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000635 AC: 15 AN: 236120 AF XY: 0.0000233

Gnomad AFR exome AF: 0.000763

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 14 AN: 638166 Hom.: 0 Cov.: 9 AF XY: 0.0000118 AC XY: 4 AN XY: 339462

African (AFR) AF: 0.000593 AC: 9 AN: 15178

American (AMR) AF: 0.0000822 AC: 3 AN: 36504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13382

East Asian (EAS) AF: 0.00 AC: 0 AN: 14228

South Asian (SAS) AF: 0.00 AC: 0 AN: 71930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 436358

Other (OTH) AF: 0.0000790 AC: 2 AN: 25304

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74464

African (AFR) AF: 0.000698 AC: 29 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	1	-	Arrhythmogenic right ventricular dysplasia 9 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.6
DANN	Benign	0.23
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
PhyloP100		0.45
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.049
Sift	Benign	0.59	T
Sift4G	Benign	0.69	T
Polyphen		0.0020	B
Vest4		0.26
MutPred		0.42		Gain of glycosylation at G488 (P = 0.0035)
MVP		0.53
MPC		0.15
ClinPred		0.0054	T
GERP RS		0.51
Varity_R		0.088
gMVP		0.23
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs537458442; hg19: chr12-32996164;