12-32791480-G-T

Variant names:

• chr12-32791480-G-T
• rs6488090
• NM_001005242.3:c.*944C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005242.3(PKP2):​c.*944C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.92 in 152,324 control chromosomes in the GnomAD database, including 64,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64619 hom., cov: 32)
  • Exomes 𝑓: 1.0 (7 hom.)
• Consequence: PKP2 NM_001005242.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.572

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-32791480-G-T is Benign according to our data. Variant chr12-32791480-G-T is described in ClinVar as [Benign]. Clinvar id is 308481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.*944C>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811	c.*944C>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.920 AC: 140076 AN: 152192 Hom.: 64581 Cov.: 32

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 0.889

Gnomad SAS AF: 0.942

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.952

Gnomad OTH AF: 0.917

GnomAD4 exome AF: 1.00 AC: 14 AN: 14 Hom.: 7 Cov.: 0 AF XY: 1.00 AC XY: 6 AN XY: 6

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.920 AC: 140173 AN: 152310 Hom.: 64619 Cov.: 32 AF XY: 0.919 AC XY: 68471 AN XY: 74476

Gnomad4 AFR AF: 0.880

Gnomad4 AMR AF: 0.870

Gnomad4 ASJ AF: 0.933

Gnomad4 EAS AF: 0.888

Gnomad4 SAS AF: 0.942

Gnomad4 FIN AF: 0.954

Gnomad4 NFE AF: 0.952

Gnomad4 OTH AF: 0.916

Alfa AF: 0.941 Hom.: 8578

Bravo AF: 0.908

Asia WGS AF: 0.887 AC: 3087 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs6488090; hg19: chr12-32944414;