2-44323389-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001171613.2(PREPL):c.1502A>G(p.Asn501Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0018 in 1,596,876 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N501N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0093 ( 22 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 30 hom. )

Consequence

PREPL
NM_001171613.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.22

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073111653).

BP6

Variant 2-44323389-T-C is Benign according to our data. Variant chr2-44323389-T-C is described in ClinVar as Benign. ClinVar VariationId is 478309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0093 (1416/152214) while in subpopulation AFR AF = 0.0322 (1337/41534). AF 95% confidence interval is 0.0308. There are 22 homozygotes in GnomAd4. There are 658 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREPL	NM_001171613.2 link	c.1502A>G	p.Asn501Ser	missense_variant	Exon 11 of 14	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6 link	c.1502A>G	p.Asn501Ser	missense_variant	Exon 11 of 14	1	NM_001171613.2	ENSP00000387095.2

Frequencies

GnomAD3 genomes

AF:

0.00922

AC:

1402

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00258

AC:

613

AN:

237496

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.0345

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.000522

GnomAD4 exome

AF:

0.00101

AC:

1457

AN:

1444662

Hom.:

Cov.:

AF XY:

0.000895

AC XY:

643

AN XY:

718404

show subpopulations

African (AFR)

AF:

0.0349

AC:

1139

AN:

32672

American (AMR)

AF:

0.00210

AC:

AN:

41480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25556

East Asian (EAS)

AF:

0.00

AC:

AN:

39338

South Asian (SAS)

AF:

0.0000605

AC:

AN:

82662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00472

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

1104234

Other (OTH)

AF:

0.00263

AC:

157

AN:

59742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00930

AC:

1416

AN:

152214

Hom.:

Cov.:

AF XY:

0.00884

AC XY:

658

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0322

AC:

1337

AN:

41534

American (AMR)

AF:

0.00346

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68006

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

135

202

270

337

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:

0.00474

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0331

AC:

146

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00305

AC:

370

Asia WGS

AF:

0.00318

AC:

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myasthenic syndrome, congenital, 22

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

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

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0073

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.73

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

PhyloP100

4.2

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.093

Sift

Benign

0.23

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

Sift4G

Benign

0.19

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

Polyphen

0.37, 0.30, 0.99

.;.;.;B;B;B;B;B;D

Vest4

0.40

MVP

0.22

MPC

0.0068

ClinPred

0.032

GERP RS

4.2

PromoterAI

0.0058

Neutral

(source)

Varity_R

0.11

gMVP

0.52

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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