rs149012504

Positions:

chr2-44321418-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001171613.2(PREPL):c.1855G>A(p.Glu619Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,692 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 10 hom. )

Consequence

PREPL
NM_001171613.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.57

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:

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

SLC3A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005270511).

BP6

Variant 2-44321418-C-T is Benign according to our data. Variant chr2-44321418-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 436413.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 = 0.00518 (787/152024) while in subpopulation AFR AF= 0.0176 (729/41456). AF 95% confidence interval is 0.0165. There are 9 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2 linkuse as main transcript	c.1855G>A	p.Glu619Lys	missense_variant	14/14	ENST00000409411.6
SLC3A1	NM_000341.4 linkuse as main transcript	c.*779C>T		3_prime_UTR_variant	10/10	ENST00000260649.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6 linkuse as main transcript	c.1855G>A	p.Glu619Lys	missense_variant	14/14	1	NM_001171613.2	P4	Q4J6C6-4
SLC3A1	ENST00000260649.11 linkuse as main transcript	c.*779C>T		3_prime_UTR_variant	10/10	1	NM_000341.4	P1	Q07837-1

Frequencies

GnomAD3 genomes

AF:

0.00516

AC:

784

AN:

151908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00141

AC:

354

AN:

250808

Hom.:

AF XY:

0.00102

AC XY:

138

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.0180

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000603

AC:

881

AN:

1460668

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

381

AN XY:

726680

show subpopulations

Gnomad4 AFR exome

AF:

0.0176

Gnomad4 AMR exome

AF:

0.000940

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00127

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.00518

AC:

787

AN:

152024

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

371

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0176

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00612

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00177

AC:

215

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myasthenic syndrome, congenital, 22

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2015

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.018

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

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.86

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

MetaRNN

Benign

0.0053

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

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.93

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

MutationTaster

Benign

0.64

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

PrimateAI

Benign

0.47

PROVEAN

Benign

0.15

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

REVEL

Benign

0.074

Sift

Benign

0.67

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

Sift4G

Benign

0.89

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

Polyphen

0.0010, 0.0020, 0.20

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

Vest4

0.28

MVP

0.19

MPC

0.0048

ClinPred

0.012

GERP RS

4.2

Varity_R

0.057

gMVP

0.34

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