rs183414126

Variant names:

• chr12-32850984-A-G
• rs183414126
• NM_001005242.3:c.1171-11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005242.3(PKP2):​c.1171-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,607,502 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (17 hom.)
• Consequence: PKP2 NM_001005242.3 intron
• Scores: Splicing: ADA: 0.0002445
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.80
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-32850984-A-G is Benign according to our data. Variant chr12-32850984-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00246 (375/152342) while in subpopulation NFE AF = 0.00395 (269/68042). AF 95% confidence interval is 0.00356. There are 0 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 375 AD gene.

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.1171-11T>C		intron	N/A	NP_001005242.2
	PKP2	NM_004572.4		c.1171-11T>C		intron	N/A	NP_004563.2
	PKP2	NM_001407155.1		c.1171-11T>C		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.1171-11T>C		intron	N/A	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.1171-11T>C		intron	N/A	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.1171-11T>C		intron	N/A	ENSP00000515065.2

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00290 AC: 726 AN: 250094 AF XY: 0.00332

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00146

Gnomad NFE exome AF: 0.00389

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00323 AC: 4694 AN: 1455160 Hom.: 17 Cov.: 29 AF XY: 0.00327 AC XY: 2369 AN XY: 724438

African (AFR) AF: 0.000570 AC: 19 AN: 33362

American (AMR) AF: 0.00257 AC: 115 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00376 AC: 324 AN: 86098

European-Finnish (FIN) AF: 0.00135 AC: 71 AN: 52742

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5744

European-Non Finnish (NFE) AF: 0.00347 AC: 3839 AN: 1106540

Other (OTH) AF: 0.00376 AC: 226 AN: 60172

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74496

African (AFR) AF: 0.000481 AC: 20 AN: 41576

American (AMR) AF: 0.00294 AC: 45 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00395 AC: 269 AN: 68042

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00258

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Arrhythmogenic right ventricular dysplasia 9 (6)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.8
DANN	Benign	0.66
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.038
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: rs183414126; hg19: chr12-33003918;