1-201283738-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001005337.3(PKP1):c.36C>T(p.Tyr12Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,826 control chromosomes in the GnomAD database, including 11,496 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2957 hom., cov: 33)

Exomes 𝑓: 0.097 ( 8539 hom. )

Consequence

PKP1
NM_001005337.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.822

Publications

16 publications found

Variant links:

Genes affected

PKP1 (HGNC:9023): (plakophilin 1) 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 be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

PKP1 Gene-Disease associations (from GenCC):

epidermolysis bullosa simplex due to plakophilin deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia

PKP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 1-201283738-C-T is Benign according to our data. Variant chr1-201283738-C-T is described in ClinVar as Benign. ClinVar VariationId is 256861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.822 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP1	NM_001005337.3 link	c.36C>T	p.Tyr12Tyr	synonymous_variant	Exon 1 of 14	ENST00000367324.8	NP_001005337.1	Q13835-2A0A024R952
PKP1	NM_000299.4 link	c.36C>T	p.Tyr12Tyr	synonymous_variant	Exon 1 of 15		NP_000290.2	Q13835-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKP1	ENST00000367324.8 link	c.36C>T	p.Tyr12Tyr	synonymous_variant	Exon 1 of 14	1	NM_001005337.3	ENSP00000356293.4	Q13835-2
PKP1	ENST00000263946.7 link	c.36C>T	p.Tyr12Tyr	synonymous_variant	Exon 1 of 15	5		ENSP00000263946.3	Q13835-1
PKP1	ENST00000352845.3 link	c.36C>T	p.Tyr12Tyr	synonymous_variant	Exon 1 of 14	5		ENSP00000295597.3	Q13835-1

Frequencies

GnomAD3 genomes

AF:

0.165

AC:

25052

AN:

152068

Hom.:

2952

Cov.:

show subpopulations

Gnomad AFR

AF:

0.340

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.0805

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.135

Gnomad MID

AF:

0.131

Gnomad NFE

AF:

0.0861

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.116

AC:

29039

AN:

250988

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.0928

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0746

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.0844

Gnomad OTH exome

AF:

0.0986

GnomAD4 exome

AF:

0.0975

AC:

142472

AN:

1461640

Hom.:

8539

Cov.:

AF XY:

0.0983

AC XY:

71494

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.347

AC:

11603

AN:

33466

American (AMR)

AF:

0.0969

AC:

4335

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2896

AN:

26128

East Asian (EAS)

AF:

0.0781

AC:

3100

AN:

39692

South Asian (SAS)

AF:

0.150

AC:

12915

AN:

86248

European-Finnish (FIN)

AF:

0.130

AC:

6918

AN:

53394

Middle Eastern (MID)

AF:

0.0825

AC:

476

AN:

5768

European-Non Finnish (NFE)

AF:

0.0842

AC:

93645

AN:

1111844

Other (OTH)

AF:

0.109

AC:

6584

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

7590

15181

22771

30362

37952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3684

7368

11052

14736

18420

<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:

0.165

AC:

25072

AN:

152186

Hom.:

2957

Cov.:

AF XY:

0.164

AC XY:

12221

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.340

AC:

14091

AN:

41482

American (AMR)

AF:

0.115

AC:

1763

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

411

AN:

3470

East Asian (EAS)

AF:

0.0801

AC:

415

AN:

5178

South Asian (SAS)

AF:

0.154

AC:

743

AN:

4826

European-Finnish (FIN)

AF:

0.135

AC:

1433

AN:

10612

Middle Eastern (MID)

AF:

0.130

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0861

AC:

5853

AN:

68008

Other (OTH)

AF:

0.127

AC:

269

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1013

2025

3038

4050

5063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.110

Hom.:

2894

Bravo

AF:

0.167

Asia WGS

AF:

0.159

AC:

554

AN:

3478

EpiCase

AF:

0.0839

EpiControl

AF:

0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermolysis bullosa simplex due to plakophilin deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.82

PromoterAI

-0.046

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over