Genetic Variant PREPL:p.Lys50Met (chr2-44359567-T-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_006036.4(PREPL):c.149A>T(p.Lys50Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,384 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0059 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 6 hom. )

Consequence

PREPL
NM_006036.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.41

Variant links:

Genes affected

PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

PREPL links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073641837).

BP6

Variant 2-44359567-T-A is Benign according to our data. Variant chr2-44359567-T-A is described in ClinVar as [Benign]. Clinvar id is 478307.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00589 (897/152314) while in subpopulation AFR AF= 0.0205 (853/41564). AF 95% confidence interval is 0.0194. There are 3 homozygotes in gnomad4. There are 423 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREPL	NM_001171613.2 link	c.-49+1813A>T		intron_variant	Intron 1 of 13	ENST00000409411.6	NP_001165084.1	Q4J6C6-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6 link	c.-49+1813A>T		intron_variant	Intron 1 of 13	1	NM_001171613.2	ENSP00000387095.2		Q4J6C6-4

Frequencies

GnomAD3 genomes

AF:

0.00589

AC:

897

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00146

AC:

367

AN:

251362

Hom.:

AF XY:

0.000972

AC XY:

132

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000579

AC:

846

AN:

1461070

Hom.:

Cov.:

AF XY:

0.000464

AC XY:

337

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.0208

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.00589

AC:

897

AN:

152314

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

423

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0205

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.000716

Hom.:

Bravo

AF:

0.00677

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00179

AC:

217

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myasthenic syndrome, congenital, 22

Benign:1

Jan 23, 2025

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

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

T;T;T;T;.;.;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.056

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.65

.;.;.;T;T;T;T

MetaRNN

Benign

0.0074

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;N;N;N;N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.94

N;N;N;N;N;N;D

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;D;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D;D;D

Polyphen

0.99

D;D;D;D;P;P;.

Vest4

0.47

MVP

0.26

MPC

0.014

ClinPred

0.029

GERP RS

2.9

Varity_R

0.13

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over