NM_001005242.3:c.2168-4G>T

Variant names:

• chr12-32796302-C-A
• rs376231586
• NM_001005242.3:c.2168-4G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001005242.3(PKP2):​c.2168-4G>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0001201
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.47
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -12 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 VariationId is 464425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.2168-4G>T		splice_region intron	N/A	NP_001005242.2
	PKP2	NM_004572.4		c.2300-4G>T		splice_region intron	N/A	NP_004563.2
	PKP2	NM_001407155.1		c.2168-3571G>T		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.2168-4G>T		splice_region intron	N/A	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.2300-4G>T		splice_region intron	N/A	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.2168-3571G>T		intron	N/A	ENSP00000515065.2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 13 AN: 141082 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000832 AC: 190 AN: 228390 AF XY: 0.000823

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00278 AC: 83 AN: 29900

American (AMR) AF: 0.00148 AC: 60 AN: 40420

Ashkenazi Jewish (ASJ) AF: 0.000639 AC: 16 AN: 25036

East Asian (EAS) AF: 0.000807 AC: 30 AN: 37178

South Asian (SAS) AF: 0.000633 AC: 51 AN: 80550

European-Finnish (FIN) AF: 0.000171 AC: 9 AN: 52770

Middle Eastern (MID) AF: 0.000543 AC: 3 AN: 5526

European-Non Finnish (NFE) AF: 0.000211 AC: 222 AN: 1053016

Other (OTH) AF: 0.000368 AC: 21 AN: 57100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000135 AC: 5 AN: 37162

American (AMR) AF: 0.00 AC: 0 AN: 14414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 3886

South Asian (SAS) AF: 0.000243 AC: 1 AN: 4108

European-Finnish (FIN) AF: 0.000443 AC: 4 AN: 9034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000454 AC: 3 AN: 66044

Other (OTH) AF: 0.00 AC: 0 AN: 1974

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00239 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 9 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.7
DANN	Benign	0.69
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs376231586; hg19: chr12-32949236;