Genetic Variant PKP3:p.Arg122Cys (chr11-396865-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_007183.4(PKP3):c.364C>T(p.Arg122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,600,020 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

PKP3
NM_007183.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.67

Publications

1 publications found

Variant links:

Genes affected

PKP3 (HGNC:9025): (plakophilin 3) 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 protein may act in cellular desmosome-dependent adhesion and signaling pathways. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

PKP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0094741285).

BP6

Variant 11-396865-C-T is Benign according to our data. Variant chr11-396865-C-T is described in ClinVar as Benign. ClinVar VariationId is 784519.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007183.4. 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
	PKP3	NM_007183.4	MANE Select	c.364C>T	p.Arg122Cys	missense	Exon 3 of 13	NP_009114.1	Q9Y446-1
	PKP3	NM_001303029.2		c.409C>T	p.Arg137Cys	missense	Exon 4 of 14	NP_001289958.1	Q9Y446-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKP3	ENST00000331563.7	TSL:1 MANE Select	c.364C>T	p.Arg122Cys	missense	Exon 3 of 13	ENSP00000331678.2	Q9Y446-1
PKP3	ENST00000527442.6	TSL:3	c.-105C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	ENSP00000435522.2	E9PRW6
PKP3	ENST00000528036.6	TSL:2	c.-105C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	ENSP00000434110.2	E9PRW6

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

351

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000721

AC:

159

AN:

220474

AF XY:

0.000567

show subpopulations

Gnomad AFR exome

AF:

0.00988

Gnomad AMR exome

AF:

0.000631

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000718

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000294

AC:

425

AN:

1447680

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

191

AN XY:

719830

show subpopulations

African (AFR)

AF:

0.00850

AC:

283

AN:

33306

American (AMR)

AF:

0.000636

AC:

AN:

44036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39354

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45864

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000595

AC:

AN:

1108528

Other (OTH)

AF:

0.000700

AC:

AN:

59960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00230

AC:

351

AN:

152340

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00794

AC:

330

AN:

41580

American (AMR)

AF:

0.000784

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00290

ESP6500AA

AF:

0.00718

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000767

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

0.90

PhyloP100

1.7

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.43

MVP

0.89

MPC

0.47

ClinPred

0.047

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.37

gMVP

0.61

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over