6-138092196-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022121.5(PERP):​c.428C>G​(p.Pro143Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,422 control chromosomes in the GnomAD database, including 257,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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: 𝑓 0.56 (24356 hom., cov: 33)
  • Exomes 𝑓: 0.56 (233078 hom.)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0780478E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

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>G	p.Pro143Arg	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>G	p.Pro143Arg	missense	Exon 3 of 3	ENSP00000397157.2	Q96FX8

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85642 AN: 151978 Hom.: 24336 Cov.: 33

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.590

GnomAD2 exomes AF: 0.588 AC: 147812 AN: 251210 AF XY: 0.597

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.726

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.562 AC: 820747 AN: 1461326 Hom.: 233078 Cov.: 57 AF XY: 0.568 AC XY: 412846 AN XY: 727008

African (AFR) AF: 0.531 AC: 17761 AN: 33470

American (AMR) AF: 0.542 AC: 24206 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 15658 AN: 26134

East Asian (EAS) AF: 0.669 AC: 26573 AN: 39696

South Asian (SAS) AF: 0.736 AC: 63450 AN: 86232

European-Finnish (FIN) AF: 0.534 AC: 28502 AN: 53412

Middle Eastern (MID) AF: 0.646 AC: 3726 AN: 5768

European-Non Finnish (NFE) AF: 0.545 AC: 605876 AN: 1111546

Other (OTH) AF: 0.580 AC: 34995 AN: 60384

GnomAD4 genome AF: 0.563 AC: 85697 AN: 152096 Hom.: 24356 Cov.: 33 AF XY: 0.569 AC XY: 42319 AN XY: 74370

African (AFR) AF: 0.535 AC: 22173 AN: 41476

American (AMR) AF: 0.581 AC: 8883 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2114 AN: 3472

East Asian (EAS) AF: 0.715 AC: 3702 AN: 5176

South Asian (SAS) AF: 0.749 AC: 3605 AN: 4816

European-Finnish (FIN) AF: 0.542 AC: 5734 AN: 10570

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37371 AN: 67988

Other (OTH) AF: 0.596 AC: 1258 AN: 2112

Alfa AF: 0.549 Hom.: 16402

Bravo AF: 0.563

TwinsUK AF: 0.538 AC: 1994

ALSPAC AF: 0.556 AC: 2141

ESP6500AA AF: 0.531 AC: 2339

ESP6500EA AF: 0.552 AC: 4745

ExAC AF: 0.590 AC: 71619

Asia WGS AF: 0.717 AC: 2492 AN: 3478

EpiCase AF: 0.567

EpiControl AF: 0.580

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.9
DANN	Benign	0.89
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.095
Sift	Benign	0.49	T
Sift4G	Benign	0.32	T
Polyphen		0.046	B
Vest4		0.062
MPC		0.64
ClinPred		0.0047	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.75
Mutation Taster		=93/7	polymorphism (auto)

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; COSMIC: COSV107520947;