rs2484066

Variant names:

• chr6-138095981-T-G
• rs2484066
• NM_022121.5:c.355+373A>C

Variant summary

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

The NM_022121.5(PERP):​c.355+373A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,984 control chromosomes in the GnomAD database, including 20,024 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20024 hom., cov: 31)
• Consequence: PERP NM_022121.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 4 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• erythrokeratodermia variabilis et progressiva 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, 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 (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 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.355+373A>C		intron	N/A	NP_071404.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PERP	ENST00000421351.4	TSL:1 MANE Select	c.355+373A>C		intron	N/A	ENSP00000397157.2	Q96FX8

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76202 AN: 151866 Hom.: 20018 Cov.: 31

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.0794

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.493

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.502 AC: 76227 AN: 151984 Hom.: 20024 Cov.: 31 AF XY: 0.491 AC XY: 36499 AN XY: 74312

African (AFR) AF: 0.529 AC: 21939 AN: 41456

American (AMR) AF: 0.367 AC: 5606 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1891 AN: 3472

East Asian (EAS) AF: 0.0794 AC: 410 AN: 5162

South Asian (SAS) AF: 0.327 AC: 1571 AN: 4804

European-Finnish (FIN) AF: 0.525 AC: 5546 AN: 10562

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.556 AC: 37755 AN: 67946

Other (OTH) AF: 0.488 AC: 1027 AN: 2104

Alfa AF: 0.525 Hom.: 33282

Bravo AF: 0.491

Asia WGS AF: 0.233 AC: 815 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.77
PhyloP100		0.024
Mutation Taster		=100/0	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: rs2484066; hg19: chr6-138417118; COSMIC: COSV69827758;