rs762704106

Variant names:

• chr2-44329014-C-T
• rs762704106
• NM_001171613.2:c.1185G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001171613.2(PREPL):​c.1185G>A​(p.Met395Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.594

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06533459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREPL	NM_001171613.2	c.1185G>A	p.Met395Ile	missense_variant	Exon 9 of 14	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6	c.1185G>A	p.Met395Ile	missense_variant	Exon 9 of 14	1	NM_001171613.2	ENSP00000387095.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251314 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Uncertain:1

Nov 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with isoleucine at codon 484 of the PREPL protein (p.Met484Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs762704106, ExAC 0.006%). This variant has not been reported in the literature in individuals with PREPL-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.014	.;.;.;T;T;T;T;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.72	T;.;.;.;.;.;T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.84	.;.;.;N;N;N;N;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.19	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.014
Sift	Benign	0.43	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.72	T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.0070, 0.0	.;.;.;B;B;B;B;B;B
Vest4		0.32
MutPred		0.44		.;.;.;Gain of ubiquitination at K487 (P = 0.2244);Gain of ubiquitination at K487 (P = 0.2244);Gain of ubiquitination at K487 (P = 0.2244);Gain of ubiquitination at K487 (P = 0.2244);.;.;
MVP		0.076
MPC		0.0048
ClinPred		0.029	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs762704106; hg19: chr2-44556153;