NM_022121.5:c.428C>T

Variant names:

• chr6-138092196-G-A
• rs648802
• NM_022121.5:c.428C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022121.5(PERP):​c.428C>T​(p.Pro143Leu) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PERP NM_022121.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249
• Publications: 41 publications found

Genes affected

PERP (HGNC:17637): (p53 apoptosis effector related to PMP22) Involved in activation of cysteine-type endopeptidase activity. Predicted to be located in plasma membrane. Predicted to be active in cell-cell junction. Implicated in erythrokeratodermia variabilis and mutilating palmoplantar keratoderma with periorificial keratotic plaques. [provided by Alliance of Genome Resources, Apr 2022]

PERP Gene-Disease associations (from GenCC):

• Olmsted syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• erythrokeratodermia variabilis et progressiva 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mutilating palmoplantar keratoderma with periorificial keratotic plaques

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08410692).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022121.5. 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
	PERP	NM_022121.5	MANE Select	c.428C>T	p.Pro143Leu	missense	Exon 3 of 3	NP_071404.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PERP	ENST00000421351.4	TSL:1 MANE Select	c.428C>T	p.Pro143Leu	missense	Exon 3 of 3	ENSP00000397157.2	Q96FX8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 16402

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.8
DANN	Benign	0.78
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.0020	B
Vest4		0.054
MutPred		0.42		Loss of sheet (P = 0.0054)
MVP		0.17
MPC		0.53
ClinPred		0.041	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.76
Mutation Taster		=92/8	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

dbSNP: rs648802; hg19: chr6-138413333;