rs75909145

Variant names:

• chr12-32896523-C-A
• rs75909145
• NM_001005242.3:c.209G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-32896523-C-A
• chr12-32896523-C-G

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.209G>T​(p.Ser70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 1,549,506 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (39 hom., cov: 33)
  • Exomes 𝑓: 0.025 (524 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.796
• Publications: 16 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000309487 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021330118).
• BP6: Variant 12-32896523-C-A is Benign according to our data. Variant chr12-32896523-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45057.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 = 0.0193 (2932/152236) while in subpopulation NFE AF = 0.0283 (1926/68008). AF 95% confidence interval is 0.0273. There are 39 homozygotes in GnomAd4. There are 1364 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2932 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.209G>T	p.Ser70Ile	missense	Exon 1 of 13	NP_001005242.2	Q99959-2
	PKP2	NM_004572.4		c.209G>T	p.Ser70Ile	missense	Exon 1 of 14	NP_004563.2	Q99959-1
	PKP2	NM_001407155.1		c.209G>T	p.Ser70Ile	missense	Exon 1 of 12	NP_001394084.1	A0A8V8TPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.209G>T	p.Ser70Ile	missense	Exon 1 of 13	ENSP00000342800.5	Q99959-2
	PKP2	ENST00000070846.11	TSL:1	c.209G>T	p.Ser70Ile	missense	Exon 1 of 14	ENSP00000070846.6	Q99959-1
	PKP2	ENST00000700559.2		c.209G>T	p.Ser70Ile	missense	Exon 1 of 12	ENSP00000515065.2	A0A8V8TPU9

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2936 AN: 152118 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00551

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.000779

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0212 AC: 3960 AN: 186782 AF XY: 0.0226

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.000378

Gnomad FIN exome AF: 0.0160

Gnomad NFE exome AF: 0.0260

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0253 AC: 35288 AN: 1397270 Hom.: 524 Cov.: 32 AF XY: 0.0254 AC XY: 17610 AN XY: 693138

African (AFR) AF: 0.00290 AC: 87 AN: 30014

American (AMR) AF: 0.0136 AC: 556 AN: 40974

Ashkenazi Jewish (ASJ) AF: 0.0402 AC: 974 AN: 24236

East Asian (EAS) AF: 0.000340 AC: 12 AN: 35324

South Asian (SAS) AF: 0.0293 AC: 2359 AN: 80404

European-Finnish (FIN) AF: 0.0156 AC: 586 AN: 37566

Middle Eastern (MID) AF: 0.0325 AC: 143 AN: 4396

European-Non Finnish (NFE) AF: 0.0268 AC: 29097 AN: 1086366

Other (OTH) AF: 0.0254 AC: 1474 AN: 57990

GnomAD4 genome AF: 0.0193 AC: 2932 AN: 152236 Hom.: 39 Cov.: 33 AF XY: 0.0183 AC XY: 1364 AN XY: 74414

African (AFR) AF: 0.00447 AC: 186 AN: 41568

American (AMR) AF: 0.0187 AC: 287 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.000781 AC: 4 AN: 5124

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4824

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1926 AN: 68008

Other (OTH) AF: 0.0223 AC: 47 AN: 2108

Alfa AF: 0.0242 Hom.: 18

Bravo AF: 0.0183

TwinsUK AF: 0.0305 AC: 113

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00368 AC: 15

ESP6500EA AF: 0.0261 AC: 212

ExAC AF: 0.0197 AC: 2330

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Arrhythmogenic right ventricular dysplasia 9 (6)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.80
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.28	B
Vest4		0.25
MPC		0.28
ClinPred		0.0029	T
GERP RS		3.2
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.43
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75909145; hg19: chr12-33049457;