rs74072938

Variant names:

• chr12-32802396-G-A
• rs74072938
• NM_001005242.3:c.2167+7C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-32802396-G-A
• chr12-32802396-G-T

Variant summary

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

The NM_004572.4(PKP2):​c.2299+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,010 control chromosomes in the GnomAD database, including 1,691 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (736 hom., cov: 32)
  • Exomes 𝑓: 0.017 (955 hom.)
• Consequence: PKP2 NM_004572.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004315
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.47
• Publications: 5 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=-0.9).
• BP6: Variant 12-32802396-G-A is Benign according to our data. Variant chr12-32802396-G-A is described in ClinVar as Benign. ClinVar VariationId is 45064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004572.4. 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.2167+7C>T		splice_region intron	N/A	NP_001005242.2
	PKP2	NM_004572.4		c.2299+7C>T		splice_region intron	N/A	NP_004563.2
	PKP2	NM_001407155.1		c.2167+7C>T		splice_region intron	N/A	NP_001394084.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.2167+7C>T		splice_region intron	N/A	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.2299+7C>T		splice_region intron	N/A	ENSP00000070846.6
	PKP2	ENST00000700559.2		c.2167+7C>T		splice_region intron	N/A	ENSP00000515065.2

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9345 AN: 151798 Hom.: 739 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.00777

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0475

GnomAD2 exomes AF: 0.0278 AC: 6997 AN: 251360 AF XY: 0.0262

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00944

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0174 AC: 25452 AN: 1461094 Hom.: 955 Cov.: 30 AF XY: 0.0177 AC XY: 12858 AN XY: 726902

African (AFR) AF: 0.192 AC: 6412 AN: 33438

American (AMR) AF: 0.0177 AC: 792 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 279 AN: 26128

East Asian (EAS) AF: 0.00131 AC: 52 AN: 39686

South Asian (SAS) AF: 0.0468 AC: 4032 AN: 86212

European-Finnish (FIN) AF: 0.00965 AC: 515 AN: 53374

Middle Eastern (MID) AF: 0.0247 AC: 142 AN: 5738

European-Non Finnish (NFE) AF: 0.0106 AC: 11726 AN: 1111434

Other (OTH) AF: 0.0249 AC: 1502 AN: 60364

GnomAD4 genome AF: 0.0616 AC: 9355 AN: 151916 Hom.: 736 Cov.: 32 AF XY: 0.0600 AC XY: 4456 AN XY: 74254

African (AFR) AF: 0.186 AC: 7681 AN: 41370

American (AMR) AF: 0.0276 AC: 422 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3464

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5162

South Asian (SAS) AF: 0.0435 AC: 209 AN: 4804

European-Finnish (FIN) AF: 0.00777 AC: 82 AN: 10554

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 787 AN: 67984

Other (OTH) AF: 0.0470 AC: 99 AN: 2106

Alfa AF: 0.0351 Hom.: 717

Bravo AF: 0.0685

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0126

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Arrhythmogenic right ventricular dysplasia 9 (4)
-	-	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	-0.90
CADD	Benign	0.89
DANN	Benign	0.43
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0060
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: rs74072938; hg19: chr12-32955330;