12-32877952-C-T

Variant names:

• chr12-32877952-C-T
• rs768396351
• NM_001005242.3:c.928G>A

Variant summary

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

The NM_001005242.3(PKP2):​c.928G>A​(p.Val310Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,614,028 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V310L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.05
• Publications: 1 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

ENSG00000309501 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054295987).
• BP6: Variant 12-32877952-C-T is Benign according to our data. Variant chr12-32877952-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201962.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000158 (24/152230) while in subpopulation AMR AF = 0.00105 (16/15282). AF 95% confidence interval is 0.000656. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 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.928G>A	p.Val310Met	missense	Exon 3 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.928G>A	p.Val310Met	missense	Exon 3 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.928G>A	p.Val310Met	missense	Exon 3 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.928G>A	p.Val310Met	missense	Exon 3 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.928G>A	p.Val310Met	missense	Exon 3 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.928G>A	p.Val310Met	missense	Exon 3 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000916 AC: 23 AN: 251022 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.0000756 AC XY: 55 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000872 AC: 97 AN: 1111986

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74368

African (AFR) AF: 0.000121 AC: 5 AN: 41468

American (AMR) AF: 0.00105 AC: 16 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.80
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.19
Sift	Benign	0.27	T
Sift4G	Benign	0.23	T
Polyphen		0.0040	B
Vest4		0.10
MutPred		0.29		Gain of helix (P = 0.0143)
MVP		0.65
MPC		0.16
ClinPred		0.029	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.35
Mutation Taster		=90/10	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: rs768396351; hg19: chr12-33030886;