rs199938599

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006036.4(PREPL):c.217A>G(p.Lys73Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,601,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K73N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

PREPL
NM_006036.4 missense, splice_region

Scores

Splicing: ADA: 0.003594

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.89

Publications

3 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), Illumina, Ambry Genetics

PREPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06994799).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006036.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PREPL	NM_001171613.2	MANE Select	c.-49+1881A>G		intron	N/A	NP_001165084.1	Q4J6C6-4
PREPL	NM_001171603.1		c.217A>G	p.Lys73Glu	missense splice_region	Exon 2 of 15	NP_001165074.1	Q4J6C6-1
PREPL	NM_001171606.2		c.217A>G	p.Lys73Glu	missense splice_region	Exon 2 of 15	NP_001165077.1	Q4J6C6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PREPL	ENST00000260648.10	TSL:1	c.217A>G	p.Lys73Glu	missense splice_region	Exon 1 of 14	ENSP00000260648.6	Q4J6C6-1
PREPL	ENST00000409936.5	TSL:1	c.217A>G	p.Lys73Glu	missense splice_region	Exon 2 of 15	ENSP00000386543.1	Q4J6C6-1
PREPL	ENST00000378511.7	TSL:1	c.217A>G	p.Lys73Glu	missense splice_region	Exon 1 of 13	ENSP00000367772.3	Q4J6C6-3

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000183

AC:

AN:

251098

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000244

AC:

354

AN:

1449652

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

169

AN XY:

721834

show subpopulations

African (AFR)

AF:

0.0000604

AC:

AN:

33116

American (AMR)

AF:

0.000291

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

85970

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5158

European-Non Finnish (NFE)

AF:

0.000292

AC:

322

AN:

1101668

Other (OTH)

AF:

0.000200

AC:

AN:

59962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000269

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41436

American (AMR)

AF:

0.00144

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68030

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Myasthenic syndrome, congenital, 22 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.77

M_CAP

Benign

0.0034

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

1.9

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.020

REVEL

Uncertain

0.31

Sift

Benign

0.035

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.58

MVP

0.29

MPC

0.0043

ClinPred

0.017

GERP RS

4.1

PromoterAI

-0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.48

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0036

dbscSNV1_RF

Benign

0.058

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over