NM_001005242.3:c.*1271G>C

Variant names:

• chr12-32791153-C-G
• rs12314796
• NM_001005242.3:c.*1271G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005242.3(PKP2):​c.*1271G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 152,104 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (254 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: PKP2 NM_001005242.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0250
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-32791153-C-G is Benign according to our data. Variant chr12-32791153-C-G is described in ClinVar as Benign. ClinVar VariationId is 308471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

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.*1271G>C		3_prime_UTR	Exon 13 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.*1271G>C		3_prime_UTR	Exon 14 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.*1126G>C		3_prime_UTR	Exon 12 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.*1271G>C		3_prime_UTR	Exon 13 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.*1271G>C		3_prime_UTR	Exon 14 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.*1126G>C		3_prime_UTR	Exon 12 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7892 AN: 151986 Hom.: 253 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0464

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0589

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0493

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0519 AC: 7888 AN: 152104 Hom.: 254 Cov.: 33 AF XY: 0.0496 AC XY: 3688 AN XY: 74324

African (AFR) AF: 0.0211 AC: 878 AN: 41524

American (AMR) AF: 0.0463 AC: 707 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5184

South Asian (SAS) AF: 0.0583 AC: 281 AN: 4820

European-Finnish (FIN) AF: 0.0269 AC: 283 AN: 10532

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0794 AC: 5399 AN: 67984

Other (OTH) AF: 0.0488 AC: 103 AN: 2112

Alfa AF: 0.0384 Hom.: 31

Bravo AF: 0.0515

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.59
PhyloP100		0.025
Mutation Taster		=100/0	polymorphism (auto)

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: rs12314796; hg19: chr12-32944087;