rs138555092

Positions:

• chr2-44343945-T-C

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.149A>G​(p.Asn50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,670 control chromosomes in the GnomAD database, including 10 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16

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 (MetaRNN=0.0030634105).
• BP6: Variant 2-44343945-T-C is Benign according to our data. Variant chr2-44343945-T-C is described in ClinVar as [Benign]. Clinvar id is 544540.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 = 0.00236 (3443/1461372) while in subpopulation MID AF= 0.00382 (22/5762). AF 95% confidence interval is 0.00258. There are 9 homozygotes in gnomad4_exome. There are 1698 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.149A>G	p.Asn50Ser	missense_variant	4/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.149A>G	p.Asn50Ser	missense_variant	4/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00233 AC: 582 AN: 250034 Hom.: 2 AF XY: 0.00239 AC XY: 323 AN XY: 135388

Gnomad AFR exome AF: 0.000569

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000928

Gnomad NFE exome AF: 0.00348

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00236 AC: 3443 AN: 1461372 Hom.: 9 Cov.: 32 AF XY: 0.00234 AC XY: 1698 AN XY: 726994

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.00255

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00115 AC XY: 86 AN XY: 74488

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00250 Hom.: 1

Bravo AF: 0.00149

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00274 AC: 332

EpiCase AF: 0.00218

EpiControl AF: 0.00225

ClinVar

Significance: 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

Invitae

Jan 22, 2024

- -

PREPL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as 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
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.062
DANN	Benign	0.88
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.74	T;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0031	T;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	0.26	T
PROVEAN	Benign	-0.13	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.31	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;.;B;B;B;B;B;B;.
Vest4		0.063
MVP		0.14
MPC		0.0055
ClinPred		0.0033	T
GERP RS		-8.6
Varity_R		0.017
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138555092; hg19: chr2-44571084; COSMIC: COSV53217039; COSMIC: COSV53217039;