rs202009058

chr2-44326704-G-Achr2-44326704-G-Cchr2-44326704-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171613.2(PREPL):c.1479+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,608,438 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (10 hom.)
• Consequence: PREPL NM_001171613.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003659
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.103

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-44326704-G-A is Benign according to our data. Variant chr2-44326704-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 544541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000662 (964/1456344) while in subpopulation MID AF= 0.00935 (48/5134). AF 95% confidence interval is 0.00725. There are 10 homozygotes in gnomad4_exome. There are 607 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.1479+8C>T		splice_region_variant, intron_variant		ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.1479+8C>T		splice_region_variant, intron_variant		1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000967 AC: 243 AN: 251316 Hom.: 3 AF XY: 0.00131 AC XY: 178 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000662 AC: 964 AN: 1456344 Hom.: 10 Cov.: 31 AF XY: 0.000837 AC XY: 607 AN XY: 724930

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00456

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.000847

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74352

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000348

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 21, 2018

- -

PREPL-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.0
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
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: rs202009058; hg19: chr2-44553843;