rs755600420

Variant names:

• chr12-32896503-A-C
• rs755600420
• NM_001005242.3:c.223+6T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32896503-A-C
• chr12-32896503-A-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004572.4(PKP2):​c.223+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000593 in 1,348,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: PKP2 NM_004572.4 splice_region, intron
• Scores: Splicing: ADA: 0.9753
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• 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

ENSG00000309487 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004572.4. 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.223+6T>G		splice_region intron	N/A	NP_001005242.2
	PKP2	NM_004572.4		c.223+6T>G		splice_region intron	N/A	NP_004563.2
	PKP2	NM_001407155.1		c.223+6T>G		splice_region intron	N/A	NP_001394084.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.223+6T>G		splice_region intron	N/A	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.223+6T>G		splice_region intron	N/A	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.223+6T>G		splice_region intron	N/A	ENSP00000515065.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000642 AC: 1 AN: 155748 AF XY: 0.0000114

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: 0.0000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000593 AC: 8 AN: 1348922 Hom.: 0 Cov.: 31 AF XY: 0.00000901 AC XY: 6 AN XY: 665660

African (AFR) AF: 0.00 AC: 0 AN: 28708

American (AMR) AF: 0.00 AC: 0 AN: 36796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22278

East Asian (EAS) AF: 0.00 AC: 0 AN: 33066

South Asian (SAS) AF: 0.00 AC: 0 AN: 74006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4200

European-Non Finnish (NFE) AF: 0.00000661 AC: 7 AN: 1058478

Other (OTH) AF: 0.0000180 AC: 1 AN: 55680

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		1.2
PromoterAI		-0.18	Neutral
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.57
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: rs755600420; hg19: chr12-33049437;