chr2-44359715-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The ENST00000260648.10(PREPL):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PREPL
ENST00000260648.10 initiator_codon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.53

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypotonia-cystinuria syndrome
Inheritance: AR Classification: STRONG Submitted by: G2P
myasthenic syndrome, congenital, 22
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Illumina

PREPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 23 codons. Genomic position: 44359649. Lost 0.031 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREPL	NM_001171613.2 link	c.-49+1665A>C		intron_variant	Intron 1 of 13	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6 link	c.-49+1665A>C		intron_variant	Intron 1 of 13	1	NM_001171613.2	ENSP00000387095.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249950

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447400

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721058

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33090

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

85894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099404

Other (OTH)

AF:

0.00

AC:

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myasthenic syndrome, congenital, 22

Uncertain:1

Jun 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 544539). This variant has not been reported in the literature in individuals affected with PREPL-related conditions. This variant is present in population databases (rs766377212, gnomAD 0.007%). This sequence change affects the initiator methionine of the PREPL mRNA. The next in-frame methionine is located at codon 23.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.0

.;.;.;D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

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

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.

PhyloP100

3.5

PROVEAN

Benign

-0.49

N;N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.92

ClinPred

0.92

GERP RS

5.3

PromoterAI

0.00070

Neutral

(source)

Varity_R

0.74

gMVP

0.35

Mutation Taster

=36/164

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over