rs142981913

chr2-44342452-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001171613.2(PREPL):c.450A>C(p.Lys150Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.222

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07309744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.450A>C	p.Lys150Asn	missense_variant	5/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.450A>C	p.Lys150Asn	missense_variant	5/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251220 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135780

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461142 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726908

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 30 AN XY: 74312

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000921 Hom.: 0

Bravo AF: 0.000480

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 06, 2022	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 239 of the PREPL protein (p.Lys239Asn). This variant is present in population databases (rs142981913, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PREPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 544537). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 23, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.717A>C (p.K239N) alteration is located in exon 5 (coding exon 5) of the PREPL gene. This alteration results from a A to C substitution at nucleotide position 717, causing the lysine (K) at amino acid position 239 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Uncertain	1.0
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D;.;.;.;.;.;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.62	D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T
Polyphen		0.084, 0.99, 0.45	.;.;.;B;B;B;B;D;B
Vest4		0.55
MutPred		0.44		.;.;.;Loss of ubiquitination at K239 (P = 0.0127);Loss of ubiquitination at K239 (P = 0.0127);Loss of ubiquitination at K239 (P = 0.0127);Loss of ubiquitination at K239 (P = 0.0127);Loss of ubiquitination at K239 (P = 0.0127);Loss of ubiquitination at K239 (P = 0.0127);
MVP		0.31
MPC		0.0049
ClinPred		0.038	T
GERP RS		-2.6
Varity_R		0.058
gMVP		0.61

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: rs142981913; hg19: chr2-44569591;