rs373399921

Variant names:

• chr12-32843271-G-A
• rs373399921
• ENST00000070846.11:c.1421C>T

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.1421C>T​(p.Ala474Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000593 in 1,331,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A474T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PKP2 NM_004572.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.526
• Publications: 6 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=0.0062630773).
• BP6: Variant 12-32843271-G-A is Benign according to our data. Variant chr12-32843271-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191765.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000151 (23/152292) while in subpopulation EAS AF = 0.00386 (20/5176). AF 95% confidence interval is 0.00256. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 23 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.1379-2066C>T		intron	N/A	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1421C>T	p.Ala474Val	missense	Exon 6 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407157.1		c.1421C>T	p.Ala474Val	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.1421C>T	p.Ala474Val	missense	Exon 6 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1379-2066C>T		intron	N/A	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000700559.2		c.1379-2066C>T		intron	N/A	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000180 AC: 44 AN: 244002 AF XY: 0.000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00230

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000475 AC: 56 AN: 1179126 Hom.: 0 Cov.: 20 AF XY: 0.0000341 AC XY: 20 AN XY: 586640

African (AFR) AF: 0.00 AC: 0 AN: 25640

American (AMR) AF: 0.00 AC: 0 AN: 37256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16698

East Asian (EAS) AF: 0.00228 AC: 38 AN: 16642

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4412

European-Non Finnish (NFE) AF: 0.00000324 AC: 3 AN: 924830

Other (OTH) AF: 0.000303 AC: 13 AN: 42870

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000533 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 9 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	PKP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.2
DANN	Benign	0.47
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.53
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.020
Sift	Benign	0.36	T
Sift4G	Benign	0.51	T
Polyphen		0.037	B
Vest4		0.19
MutPred		0.32		Gain of MoRF binding (P = 0.1163)
MVP		0.23
MPC		0.16
ClinPred		0.016	T
GERP RS		-1.7
Varity_R		0.021
gMVP		0.18
Mutation Taster		=97/3	polymorphism

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: rs373399921; hg19: chr12-32996205; COSMIC: COSV105024644;