Genetic Variant NM_022121.5:c.355+76A>G (chr6-138096278-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022121.5(PERP):c.355+76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,531,570 control chromosomes in the GnomAD database, including 160,275 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 0.40 ( 13272 hom., cov: 32)

Exomes 𝑓: 0.45 ( 147003 hom. )

Consequence

PERP
NM_022121.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.200

Publications

5 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Ambry Genetics
mutilating palmoplantar keratoderma with periorificial keratotic plaques
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PERP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PERP	NM_022121.5 link	c.355+76A>G		intron_variant	Intron 2 of 2	ENST00000421351.4	NP_071404.2	Q96FX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PERP	ENST00000421351.4 link	c.355+76A>G		intron_variant	Intron 2 of 2	1	NM_022121.5	ENSP00000397157.2		Q96FX8

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61416

AN:

151914

Hom.:

13264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.345

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.0513

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.485

Gnomad OTH

AF:

0.442

GnomAD4 exome

AF:

0.452

AC:

623677

AN:

1379536

Hom.:

147003

AF XY:

0.450

AC XY:

307744

AN XY:

684260

show subpopulations

African (AFR)

AF:

0.349

AC:

10877

AN:

31204

American (AMR)

AF:

0.285

AC:

10914

AN:

38308

Ashkenazi Jewish (ASJ)

AF:

0.542

AC:

12576

AN:

23198

East Asian (EAS)

AF:

0.0783

AC:

3055

AN:

39018

South Asian (SAS)

AF:

0.302

AC:

23458

AN:

77562

European-Finnish (FIN)

AF:

0.393

AC:

20207

AN:

51460

Middle Eastern (MID)

AF:

0.498

AC:

2688

AN:

5402

European-Non Finnish (NFE)

AF:

0.488

AC:

514930

AN:

1056140

Other (OTH)

AF:

0.436

AC:

24972

AN:

57244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

15936

31872

47809

63745

79681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14872

29744

44616

59488

74360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.404

AC:

61450

AN:

152034

Hom.:

13272

Cov.:

AF XY:

0.394

AC XY:

29315

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.343

AC:

14207

AN:

41458

American (AMR)

AF:

0.345

AC:

5267

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1871

AN:

3468

East Asian (EAS)

AF:

0.0516

AC:

266

AN:

5158

South Asian (SAS)

AF:

0.292

AC:

1405

AN:

4810

European-Finnish (FIN)

AF:

0.383

AC:

4055

AN:

10584

Middle Eastern (MID)

AF:

0.524

AC:

153

AN:

292

European-Non Finnish (NFE)

AF:

0.485

AC:

32984

AN:

67962

Other (OTH)

AF:

0.438

AC:

923

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1814

3627

5441

7254

9068

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.454

Hom.:

46598

Bravo

AF:

0.400

Asia WGS

AF:

0.195

AC:

681

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.0

(source)

DANN

Benign

0.50

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over