12-42384954-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_201439.2(PPHLN1):ā€‹c.526G>Cā€‹(p.Gly176Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,611,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000044 ( 0 hom. )

Consequence

PPHLN1
NM_201439.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79
Variant links:
Genes affected
PPHLN1 (HGNC:19369): (periphilin 1) The protein encoded by this gene is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19491082).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPHLN1NM_201439.2 linkuse as main transcriptc.526G>C p.Gly176Arg missense_variant 6/10 ENST00000358314.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPHLN1ENST00000358314.12 linkuse as main transcriptc.526G>C p.Gly176Arg missense_variant 6/102 NM_201439.2 A1Q8NEY8-8

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251390
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000439
AC:
64
AN:
1458998
Hom.:
0
Cov.:
30
AF XY:
0.0000496
AC XY:
36
AN XY:
726078
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000568
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 15, 2023The c.526G>C (p.G176R) alteration is located in exon 6 (coding exon 5) of the PPHLN1 gene. This alteration results from a G to C substitution at nucleotide position 526, causing the glycine (G) at amino acid position 176 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
0.19
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.011
T;.;T;.;T;.;T;.;.
Eigen
Benign
-0.031
Eigen_PC
Benign
0.069
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;.;D;.
M_CAP
Benign
0.0038
T
MetaRNN
Benign
0.19
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.7
.;.;.;.;L;L;L;.;.
MutationTaster
Benign
0.92
D;D;D;D;N;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.59
N;N;N;.;.;N;N;N;N
REVEL
Benign
0.031
Sift
Benign
0.41
T;T;T;.;.;T;T;T;T
Sift4G
Benign
0.50
T;.;T;T;T;T;T;.;T
Polyphen
0.42
B;B;P;D;P;.;P;B;D
Vest4
0.52
MutPred
0.25
.;.;.;.;Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);.;.;
MVP
0.65
MPC
0.50
ClinPred
0.53
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.054
gMVP
0.25

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: rs763250965; hg19: chr12-42778756; API