NM_201439.2:c.498G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q166R) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201439.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPHLN1	NM_201439.2	MANE Select	c.498G>C	p.Gln166His	missense	Exon 5 of 10	NP_958847.1	Q8NEY8-8
	PPHLN1	NM_001364827.2		c.498G>C	p.Gln166His	missense	Exon 5 of 12	NP_001351756.1
	PPHLN1	NM_016488.7		c.498G>C	p.Gln166His	missense	Exon 5 of 13	NP_057572.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPHLN1	ENST00000358314.12	TSL:2 MANE Select	c.498G>C	p.Gln166His	missense	Exon 5 of 10	ENSP00000351066.7	Q8NEY8-8
	PPHLN1	ENST00000395568.6	TSL:1	c.498G>C	p.Gln166His	missense	Exon 5 of 13	ENSP00000378935.2	Q8NEY8-1
	PPHLN1	ENST00000432191.6	TSL:1	c.333G>C	p.Gln111His	missense	Exon 4 of 12	ENSP00000393965.2	Q8NEY8-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.18
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.018	D
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.28		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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chr12-42768863;