chr2-44323296-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001171613.2(PREPL):c.1595A>G(p.Lys532Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,607,868 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K532E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 1 hom. )

Consequence

PREPL
NM_001171613.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.94

Publications

4 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00668478).

BP6

Variant 2-44323296-T-C is Benign according to our data. Variant chr2-44323296-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00223 (339/152236) while in subpopulation AMR AF = 0.00523 (80/15288). AF 95% confidence interval is 0.00431. There are 1 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREPL	NM_001171613.2 link	c.1595A>G	p.Lys532Arg	missense_variant	Exon 11 of 14	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.1595A>G	p.Lys532Arg	missense_variant	Exon 11 of 14	1	NM_001171613.2	ENSP00000387095.2		Q4J6C6-4

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

339

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00462

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00159

AC:

396

AN:

249436

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.00364

Gnomad AMR exome

AF:

0.00401

Gnomad ASJ exome

AF:

0.00577

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000990

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.000911

AC:

1326

AN:

1455632

Hom.:

Cov.:

AF XY:

0.000901

AC XY:

653

AN XY:

724418

show subpopulations

African (AFR)

AF:

0.00430

AC:

143

AN:

33258

American (AMR)

AF:

0.00406

AC:

180

AN:

44376

Ashkenazi Jewish (ASJ)

AF:

0.00510

AC:

133

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39548

South Asian (SAS)

AF:

0.000432

AC:

AN:

85628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00591

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000586

AC:

649

AN:

1107476

Other (OTH)

AF:

0.00249

AC:

150

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00223

AC:

339

AN:

152236

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00426

AC:

177

AN:

41540

American (AMR)

AF:

0.00523

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00462

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68012

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00156

AC:

190

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00104

EpiControl

AF:

0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PREPL p.Lys532Arg variant was not identified in the literature but was identified in dbSNP (ID: rs111438719) and ClinVar (classified as likely benign by Invitae and as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 433 of 280810 chromosomes (1 homozygous) at a frequency of 0.001542 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 60 of 10336 chromosomes (freq: 0.005805), Latino in 142 of 35010 chromosomes (freq: 0.004056), African in 84 of 24904 chromosomes (freq: 0.003373), Other in 18 of 7174 chromosomes (freq: 0.002509), European (non-Finnish) in 116 of 128520 chromosomes (freq: 0.000903) and South Asian in 13 of 30024 chromosomes (freq: 0.000433), but was not observed in the East Asian or European (Finnish) populations. The p.Lys532 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PREPL: BP4, BS2 -

Myasthenic syndrome, congenital, 22

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

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

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;.;.;.;D;.;.;T;T;T

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.41

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

PhyloP100

4.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.26

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

REVEL

Benign

0.056

Sift

Benign

0.054

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

Sift4G

Benign

0.26

T;T;T;T;D;T;T;T;T;T

Polyphen

0.59, 0.18, 0.99

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

Vest4

0.27

MVP

0.20

MPC

0.0057

ClinPred

0.028

GERP RS

4.3

PromoterAI

0.0043

Neutral

(source)

Varity_R

0.050

gMVP

0.44

Mutation Taster

=96/4

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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chr2-44323296-T-C

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