12-42375061-G-C

Variant names:

• chr12-42375061-G-C
• NM_201439.2:c.498G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_201439.2(PPHLN1):​c.498G>C​(p.Gln166His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PPHLN1 NM_201439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.185

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29076266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPHLN1	NM_201439.2	c.498G>C	p.Gln166His	missense_variant	Exon 5 of 10	ENST00000358314.12	NP_958847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPHLN1	ENST00000358314.12	c.498G>C	p.Gln166His	missense_variant	Exon 5 of 10	2	NM_201439.2	ENSP00000351066.7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.498G>C (p.Q166H) alteration is located in exon 5 (coding exon 4) of the PPHLN1 gene. This alteration results from a G to C substitution at nucleotide position 498, causing the glutamine (Q) at amino acid position 166 to be replaced by a histidine (H). 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	0.33
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.;T;.;.;T;.;T;.;.;.;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;.;D;.;D;D;.;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	.;.;.;M;.;M;M;M;.;M;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;D;D;.;.;.;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.018	D;D;D;.;.;.;D;D;D;D;D;D;D;D
Sift4G	Benign	0.089	T;.;T;T;T;D;T;D;T;T;.;.;T;T
Polyphen		1.0	D;D;D;.;D;D;D;D;D;.;D;D;D;.
Vest4		0.56
MutPred		0.28		.;.;.;Gain of catalytic residue at Q166 (P = 0.0999);.;Gain of catalytic residue at Q166 (P = 0.0999);Gain of catalytic residue at Q166 (P = 0.0999);Gain of catalytic residue at Q166 (P = 0.0999);.;Gain of catalytic residue at Q166 (P = 0.0999);.;.;.;Gain of catalytic residue at Q166 (P = 0.0999);
MVP		0.58
MPC		0.76
ClinPred		0.96	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.34

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: chr12-42768863;