rs775519219

Variant names:

• chr12-32792719-G-C
• rs775519219
• NM_001005242.3:c.2370C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32792719-G-C
• chr12-32792719-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005242.3(PKP2):​c.2370C>G​(p.Asn790Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N790S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.65
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1592657).

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.2370C>G	p.Asn790Lys	missense	Exon 12 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.2502C>G	p.Asn834Lys	missense	Exon 13 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.2180C>G	p.Thr727Arg	missense	Exon 11 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.2370C>G	p.Asn790Lys	missense	Exon 12 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.2502C>G	p.Asn834Lys	missense	Exon 13 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.2180C>G	p.Thr727Arg	missense	Exon 11 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251398 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461622 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular dysplasia 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.046
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.7
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.050
Sift	Benign	0.54	T
Sift4G	Benign	0.15	T
Polyphen		0.22	B
Vest4		0.42
MutPred		0.30		Loss of ubiquitination at K835 (P = 0.0286)
MVP		0.66
MPC		0.22
ClinPred		0.29	T
GERP RS		3.7
Varity_R		0.060
gMVP		0.20
Mutation Taster		=79/21	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: rs775519219; hg19: chr12-32945653;