Variant 16-4883544-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002705.5(PPL):c.5111A>G(p.Asn1704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PPL
NM_002705.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0310

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030769229).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPL	NM_002705.5 linkuse as main transcript	c.5111A>G	p.Asn1704Ser	missense_variant	22/22	ENST00000345988.7	NP_002696.4
PPL	XM_017023374.3 linkuse as main transcript	c.5198A>G	p.Asn1733Ser	missense_variant	22/22		XP_016878863.1
PPL	XM_017023375.3 linkuse as main transcript	c.5159A>G	p.Asn1720Ser	missense_variant	22/22		XP_016878864.1
PPL	XM_006720902.5 linkuse as main transcript	c.5150A>G	p.Asn1717Ser	missense_variant	22/22		XP_006720965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PPL	ENST00000345988.7 linkuse as main transcript	c.5111A>G	p.Asn1704Ser	missense_variant	22/22	1	NM_002705.5	ENSP00000340510	P3
PPL	ENST00000590782.6 linkuse as main transcript	c.5105A>G	p.Asn1702Ser	missense_variant	22/22	5		ENSP00000465640	A1
PPL	ENST00000592772.1 linkuse as main transcript			downstream_gene_variant		5		ENSP00000467699

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251326

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000479

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.5111A>G (p.N1704S) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a A to G substitution at nucleotide position 5111, causing the asparagine (N) at amino acid position 1704 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.9

DANN

Benign

0.69

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.44

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.59

N;.

REVEL

Benign

0.018

Sift

Benign

0.82

T;.

Sift4G

Benign

0.39

T;T

Polyphen

0.0020

B;.

Vest4

0.085

MutPred

0.28

Gain of sheet (P = 0.0016);.;

MVP

0.45

MPC

0.018

ClinPred

0.029

GERP RS

-0.40

Varity_R

0.10

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over