chr16-4883623-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000345988.7(PPL):​c.5032G>C​(p.Gly1678Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PPL
ENST00000345988.7 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PPLNM_002705.5 linkuse as main transcriptc.5032G>C p.Gly1678Arg missense_variant 22/22 ENST00000345988.7 NP_002696.4
PPLXM_017023374.3 linkuse as main transcriptc.5119G>C p.Gly1707Arg missense_variant 22/22 XP_016878863.1
PPLXM_017023375.3 linkuse as main transcriptc.5080G>C p.Gly1694Arg missense_variant 22/22 XP_016878864.1
PPLXM_006720902.5 linkuse as main transcriptc.5071G>C p.Gly1691Arg missense_variant 22/22 XP_006720965.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPLENST00000345988.7 linkuse as main transcriptc.5032G>C p.Gly1678Arg missense_variant 22/221 NM_002705.5 ENSP00000340510 P3
PPLENST00000590782.6 linkuse as main transcriptc.5026G>C p.Gly1676Arg missense_variant 22/225 ENSP00000465640 A1
PPLENST00000592772.1 linkuse as main transcriptc.3295G>C p.Gly1099Arg missense_variant 10/105 ENSP00000467699

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsMay 28, 2024The c.5032G>C (p.G1678R) alteration is located in exon 22 (coding exon 22) of the PPL gene. This alteration results from a G to C substitution at nucleotide position 5032, causing the glycine (G) at amino acid position 1678 to be replaced by an arginine (R). 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
0.28
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.89
D;.;T
Eigen
Benign
0.14
Eigen_PC
Benign
0.066
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Uncertain
0.094
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Uncertain
0.17
D
MutationAssessor
Pathogenic
3.0
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-6.9
D;.;.
REVEL
Uncertain
0.50
Sift
Uncertain
0.026
D;.;.
Sift4G
Benign
0.11
T;T;.
Polyphen
0.74
P;.;.
Vest4
0.53
MutPred
0.68
Gain of MoRF binding (P = 0.0422);.;.;
MVP
0.93
MPC
0.042
ClinPred
0.94
D
GERP RS
3.7
Varity_R
0.65
gMVP
0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-4933624; API