rs773867044

Positions:

• chr2-44323371-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T507A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09

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 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	UniProt
PREPL	NM_001171613.2	c.1520C>A	p.Thr507Lys	missense_variant	11/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.1520C>A	p.Thr507Lys	missense_variant	11/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152072 Hom.: 0 Cov.: 32

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: 89 AN: 249448 Hom.: 0 AF XY: 0.000482 AC XY: 65 AN XY: 134744

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.: 1 Cov.: 31 AF XY: 0.000276 AC XY: 200 AN XY: 723750

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: 16 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74416

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.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.00144 AC: 5 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

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	Invitae	Oct 02, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.88	D;.;.;.;.;.;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.028	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs773867044; hg19: chr2-44550510;