Genetic Variant PPL:p.Asp1694Glu (chr16-4883573-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002705.5(PPL):c.5082C>G(p.Asp1694Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PPL
NM_002705.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.17

Publications

0 publications found

Variant links:

Genes affected

PPL (HGNC:9273): (periplakin) The protein encoded by this gene is a component of desmosomes and of the epidermal cornified envelope in keratinocytes. The N-terminal domain of this protein interacts with the plasma membrane and its C-terminus interacts with intermediate filaments. Through its rod domain, this protein forms complexes with envoplakin. This protein may serve as a link between the cornified envelope and desmosomes as well as intermediate filaments. AKT1/PKB, a protein kinase mediating a variety of cell growth and survival signaling processes, is reported to interact with this protein, suggesting a possible role for this protein as a localization signal in AKT1-mediated signaling. [provided by RefSeq, Jul 2008]

PPL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002705.5. 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
	PPL	NM_002705.5	MANE Select	c.5082C>G	p.Asp1694Glu	missense	Exon 22 of 22	NP_002696.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPL	ENST00000345988.7	TSL:1 MANE Select	c.5082C>G	p.Asp1694Glu	missense	Exon 22 of 22	ENSP00000340510.2	O60437
PPL	ENST00000950847.1		c.5130C>G	p.Asp1710Glu	missense	Exon 22 of 22	ENSP00000620906.1
PPL	ENST00000923224.1		c.5079C>G	p.Asp1693Glu	missense	Exon 22 of 22	ENSP00000593283.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251322

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.78

PhyloP100

4.2

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.86

MutPred

0.37

Gain of sheet (P = 0.0827)

MVP

0.65

MPC

0.16

ClinPred

0.83

GERP RS

5.7

Varity_R

0.83

gMVP

0.49

Mutation Taster

=42/58

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over