NM_001005242.3:c.1481G>C

Variant names:

• chr12-32841103-C-G
• rs193922672
• NM_001005242.3:c.1481G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001005242.3(PKP2):​c.1481G>C​(p.Trp494Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.1481G>C	p.Trp494Ser	missense	Exon 6 of 13	NP_001005242.2
	PKP2	NM_004572.4		c.1613G>C	p.Trp538Ser	missense	Exon 7 of 14	NP_004563.2
	PKP2	NM_001407155.1		c.1481G>C	p.Trp494Ser	missense	Exon 6 of 12	NP_001394084.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.1481G>C	p.Trp494Ser	missense	Exon 6 of 13	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.1613G>C	p.Trp538Ser	missense	Exon 7 of 14	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.1481G>C	p.Trp494Ser	missense	Exon 6 of 12	ENSP00000515065.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726802

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111082

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.9	M
PhyloP100		3.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.60		Gain of disorder (P = 0.0019)
MVP		0.96
MPC		0.82
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.80
Mutation Taster		=71/29	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: rs193922672; hg19: chr12-32994037;