rs756376477

Variant names:

• chr12-32878150-G-C
• rs756376477
• NM_001005242.3:c.730C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32878150-G-C
• chr12-32878150-G-A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.730C>G​(p.Pro244Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P244R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.88
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1807135).
• BP6: Variant 12-32878150-G-C is Benign according to our data. Variant chr12-32878150-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235044.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000026 (38/1461886) while in subpopulation AMR AF = 0.000716 (32/44722). AF 95% confidence interval is 0.00052. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 38 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.730C>G	p.Pro244Ala	missense	Exon 3 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.730C>G	p.Pro244Ala	missense	Exon 3 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.730C>G	p.Pro244Ala	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.730C>G	p.Pro244Ala	missense	Exon 3 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.730C>G	p.Pro244Ala	missense	Exon 3 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.730C>G	p.Pro244Ala	missense	Exon 3 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251262 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727246

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

American (AMR) AF: 0.000716 AC: 32 AN: 44722

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: 86258

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

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000988 AC: 12

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 9 (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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.26
Sift	Benign	0.055	T
Sift4G	Uncertain	0.046	D
Polyphen		0.95	P
Vest4		0.33
MutPred		0.31		Loss of glycosylation at P244 (P = 0.0407)
MVP		0.87
MPC		0.58
ClinPred		0.22	T
GERP RS		4.9
Varity_R		0.072
gMVP		0.37
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs756376477; hg19: chr12-33031084;