rs376231586

chr12-32796302-C-Achr12-32796302-C-Gchr12-32796302-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001005242.3(PKP2):c.2168-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKP2 NM_001005242.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001201
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.47

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-32796302-C-A is Benign according to our data. Variant chr12-32796302-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 464425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32796302-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.2168-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2168-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13 AN: 141082 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000243

Gnomad FIN AF: 0.000443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000454

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000832 AC: 190 AN: 228390 Hom.: 0 AF XY: 0.000823 AC XY: 102 AN XY: 123904

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000355

Gnomad ASJ exome AF: 0.000644

Gnomad EAS exome AF: 0.00328

Gnomad SAS exome AF: 0.000650

Gnomad FIN exome AF: 0.000615

Gnomad NFE exome AF: 0.000657

Gnomad OTH exome AF: 0.000726

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000358 AC: 495 AN: 1381496 Hom.: 0 Cov.: 32 AF XY: 0.000333 AC XY: 230 AN XY: 690210

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000639

Gnomad4 EAS exome AF: 0.000807

Gnomad4 SAS exome AF: 0.000633

Gnomad4 FIN exome AF: 0.000171

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.000368

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000921 AC: 13 AN: 141184 Hom.: 0 Cov.: 32 AF XY: 0.0000586 AC XY: 4 AN XY: 68232

Gnomad4 AFR AF: 0.000135

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000243

Gnomad4 FIN AF: 0.000443

Gnomad4 NFE AF: 0.0000454

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00239 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.7
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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: rs376231586; hg19: chr12-32949236;