Genetic Variant NM_022121.5:c.99C>T (chr6-138107242-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_022121.5(PERP):c.99C>T(p.Arg33Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,612,250 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0075 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 80 hom. )

Consequence

PERP
NM_022121.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.21

Publications

3 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 6-138107242-G-A is Benign according to our data. Variant chr6-138107242-G-A is described in ClinVar as [Benign]. Clinvar id is 710628.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00749 (1141/152324) while in subpopulation NFE AF = 0.0113 (772/68028). AF 95% confidence interval is 0.0107. There are 6 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PERP	NM_022121.5 link	c.99C>T	p.Arg33Arg	synonymous_variant	Exon 1 of 3	ENST00000421351.4	NP_071404.2	Q96FX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PERP	ENST00000421351.4 link	c.99C>T	p.Arg33Arg	synonymous_variant	Exon 1 of 3	1	NM_022121.5	ENSP00000397157.2		Q96FX8

Frequencies

GnomAD3 genomes

AF:

0.00752

AC:

1144

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00813

AC:

1969

AN:

242312

AF XY:

0.00864

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00783

Gnomad ASJ exome

AF:

0.00741

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00602

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00968

AC:

14129

AN:

1459926

Hom.:

Cov.:

AF XY:

0.00970

AC XY:

7042

AN XY:

726310

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

33444

American (AMR)

AF:

0.00848

AC:

379

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00640

AC:

167

AN:

26098

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39676

South Asian (SAS)

AF:

0.00820

AC:

707

AN:

86240

European-Finnish (FIN)

AF:

0.00720

AC:

375

AN:

52080

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0107

AC:

11891

AN:

1111654

Other (OTH)

AF:

0.00814

AC:

491

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

824

1648

2473

3297

4121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.00749

AC:

1141

AN:

152324

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41586

American (AMR)

AF:

0.00947

AC:

145

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00911

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00452

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0113

AC:

772

AN:

68028

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0102

Hom.:

Bravo

AF:

0.00716

EpiCase

AF:

0.0109

EpiControl

AF:

0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

1.2

PromoterAI

0.0054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Mutation Taster

=100/0

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over