rs773867044

Positions:

chr2-44323371-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_001171613.2(PREPL):c.1520C>A(p.Thr507Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,606,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

PREPL
NM_001171613.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02763182).

BP6

Variant 2-44323371-G-T is Benign according to our data. Variant chr2-44323371-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 478311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000205 (298/1454282) while in subpopulation SAS AF= 0.00242 (207/85610). AF 95% confidence interval is 0.00215. There are 1 homozygotes in gnomad4_exome. There are 200 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PREPL	NM_001171613.2 linkuse as main transcript	c.1520C>A	p.Thr507Lys	missense_variant	11/14	ENST00000409411.6	NP_001165084.1	Q4J6C6-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6 linkuse as main transcript	c.1520C>A	p.Thr507Lys	missense_variant	11/14	1	NM_001171613.2	ENSP00000387095.2		Q4J6C6-4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000357

AC:

AN:

249448

Hom.:

AF XY:

0.000482

AC XY:

AN XY:

134744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00250

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000796

Gnomad OTH exome

AF:

0.000658

GnomAD4 exome

AF:

0.000205

AC:

298

AN:

1454282

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

200

AN XY:

723750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00242

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000560

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000105

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000362

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.000219

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myasthenic syndrome, congenital, 22

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 02, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.048

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

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.028

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.028

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;.;L;L;L;L;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.064

Sift

Benign

0.056

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

Sift4G

Benign

0.45

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

Polyphen

0.0020, 0.0030, 0.021

.;.;.;B;B;B;B;B;B

Vest4

0.45

MutPred

0.62

.;.;.;Gain of ubiquitination at T596 (P = 0.0211);Gain of ubiquitination at T596 (P = 0.0211);Gain of ubiquitination at T596 (P = 0.0211);Gain of ubiquitination at T596 (P = 0.0211);.;.;

MVP

0.25

MPC

0.0062

ClinPred

0.017

GERP RS

2.4

Varity_R

0.077

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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