rs375292548

chr2-44323293-C-Achr2-44323293-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001171613.2(PREPL):c.1598G>T(p.Arg533Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,606,356 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R533C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.778

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06477547).
• BP6: Variant 2-44323293-C-A is Benign according to our data. Variant chr2-44323293-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544545.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.1598G>T	p.Arg533Leu	missense_variant	11/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.1598G>T	p.Arg533Leu	missense_variant	11/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151876 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

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: 0.000177

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000153 AC: 38 AN: 248420 Hom.: 1 AF XY: 0.000127 AC XY: 17 AN XY: 134302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000412

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1454364 Hom.: 1 Cov.: 30 AF XY: 0.000102 AC XY: 74 AN XY: 723720

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.000430

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000197 AC: 30 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74288

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000219

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.1865G>T (p.R622L) alteration is located in exon 11 (coding exon 11) of the PREPL gene. This alteration results from a G to T substitution at nucleotide position 1865, causing the arginine (R) at amino acid position 622 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Myasthenic syndrome, congenital, 22 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;.;.;.;D;.;.;T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.90	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.24	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.076	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;.;B;B;B;B;B
Vest4		0.36
MVP		0.32
MPC		0.0046
ClinPred		0.051	T
GERP RS		2.6
Varity_R		0.048
gMVP		0.59

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

Other links and lift over

dbSNP: rs375292548; hg19: chr2-44550432;