chr12-32850772-T-C

Variant names:

• chr12-32850772-T-C
• rs199571473
• NM_001005242.3:c.1372A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.1372A>G​(p.Ile458Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,611,984 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts 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. I458L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (13 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.40
• Publications: 7 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_001005242.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009797215).
• BP6: Variant 12-32850772-T-C is Benign according to our data. Variant chr12-32850772-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45021.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000361 (55/152250) while in subpopulation SAS AF = 0.00954 (46/4822). AF 95% confidence interval is 0.00735. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 55 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.1372A>G	p.Ile458Val	missense	Exon 5 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.1372A>G	p.Ile458Val	missense	Exon 5 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.1372A>G	p.Ile458Val	missense	Exon 5 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.1372A>G	p.Ile458Val	missense	Exon 5 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.1372A>G	p.Ile458Val	missense	Exon 5 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.1372A>G	p.Ile458Val	missense	Exon 5 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00110 AC: 275 AN: 250900 AF XY: 0.00165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000619 AC: 904 AN: 1459734 Hom.: 13 Cov.: 31 AF XY: 0.000925 AC XY: 672 AN XY: 726218

African (AFR) AF: 0.0000898 AC: 3 AN: 33420

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00948 AC: 817 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00307 AC: 14 AN: 4558

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111386

Other (OTH) AF: 0.000647 AC: 39 AN: 60238

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74422

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00954 AC: 46 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

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

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.054
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.73	N
PhyloP100		3.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.24
Sift	Benign	0.33	T
Sift4G	Benign	0.10	T
Polyphen		0.78	P
Vest4		0.36
MVP		0.56
MPC		0.53
ClinPred		0.058	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.12
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199571473; hg19: chr12-33003706;