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GeneBe

16-4883408-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_002705.5(PPL):c.5247G>C(p.Ala1749=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,614,144 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0030 ( 16 hom. )

Consequence

PPL
NM_002705.5 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.85
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-4883408-C-G is Benign according to our data. Variant chr16-4883408-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2646162.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.85 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPLNM_002705.5 linkuse as main transcriptc.5247G>C p.Ala1749= synonymous_variant 22/22 ENST00000345988.7
PPLXM_017023374.3 linkuse as main transcriptc.5334G>C p.Ala1778= synonymous_variant 22/22
PPLXM_017023375.3 linkuse as main transcriptc.5295G>C p.Ala1765= synonymous_variant 22/22
PPLXM_006720902.5 linkuse as main transcriptc.5286G>C p.Ala1762= synonymous_variant 22/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPLENST00000345988.7 linkuse as main transcriptc.5247G>C p.Ala1749= synonymous_variant 22/221 NM_002705.5 P3
PPLENST00000590782.6 linkuse as main transcriptc.5241G>C p.Ala1747= synonymous_variant 22/225 A1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00217
AC:
330
AN:
152196
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000652
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00406
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00113
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00317
Gnomad OTH
AF:
0.00573
GnomAD3 exomes
AF:
0.00226
AC:
569
AN:
251354
Hom.:
4
AF XY:
0.00238
AC XY:
323
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.000985
Gnomad AMR exome
AF:
0.00133
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000849
Gnomad FIN exome
AF:
0.00204
Gnomad NFE exome
AF:
0.00368
Gnomad OTH exome
AF:
0.00293
GnomAD4 exome
AF:
0.00305
AC:
4455
AN:
1461830
Hom.:
16
Cov.:
34
AF XY:
0.00299
AC XY:
2171
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.000597
Gnomad4 AMR exome
AF:
0.00197
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000870
Gnomad4 FIN exome
AF:
0.00234
Gnomad4 NFE exome
AF:
0.00353
Gnomad4 OTH exome
AF:
0.00371
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00217
AC:
330
AN:
152314
Hom.:
3
Cov.:
32
AF XY:
0.00211
AC XY:
157
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.000650
Gnomad4 AMR
AF:
0.00405
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00113
Gnomad4 NFE
AF:
0.00318
Gnomad4 OTH
AF:
0.00567
Alfa
AF:
0.00210
Hom.:
0
Bravo
AF:
0.00277
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00284
EpiControl
AF:
0.00213

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022PPL: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
Cadd
Benign
0.074
Dann
Benign
0.72

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.

Other links and lift over

dbSNP: rs116861592; hg19: chr16-4933409; API