rs113272276

Positions:

• chr2-44339162-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_001171613.2(PREPL):​c.687A>G​(p.Glu229=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,910 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: PREPL NM_001171613.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.651

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-44339162-T-C is Benign according to our data. Variant chr2-44339162-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.651 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00215 (327/152256) while in subpopulation AMR AF= 0.00451 (69/15292). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PREPL	NM_001171613.2	c.687A>G	p.Glu229=	synonymous_variant	6/14	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6	c.687A>G	p.Glu229=	synonymous_variant	6/14	1	NM_001171613.2	ENSP00000387095	P4

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00152 AC: 382 AN: 251098 Hom.: 1 AF XY: 0.00141 AC XY: 192 AN XY: 135716

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00371

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.000915 AC: 1337 AN: 1461654 Hom.: 2 Cov.: 31 AF XY: 0.000897 AC XY: 652 AN XY: 727106

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000584

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74442

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00267

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

PREPL: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.5
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs113272276; hg19: chr2-44566301;