rs111438719

chr2-44323296-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001171613.2(PREPL):c.1595A>G(p.Lys532Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,607,868 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K532E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (1 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.94

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00668478).
• BP6: Variant 2-44323296-T-C is Benign according to our data. Variant chr2-44323296-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00223 (339/152236) while in subpopulation AMR AF= 0.00523 (80/15288). AF 95% confidence interval is 0.00431. There are 1 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREPL	NM_001171613.2	c.1595A>G	p.Lys532Arg	missense_variant	11/14	ENST00000409411.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREPL	ENST00000409411.6	c.1595A>G	p.Lys532Arg	missense_variant	11/14	1	NM_001171613.2	P4

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152118 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00159 AC: 396 AN: 249436 Hom.: 1 AF XY: 0.00150 AC XY: 202 AN XY: 134842

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000990

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.000911 AC: 1326 AN: 1455632 Hom.: 1 Cov.: 30 AF XY: 0.000901 AC XY: 653 AN XY: 724418

Gnomad4 AFR exome AF: 0.00430

Gnomad4 AMR exome AF: 0.00406

Gnomad4 ASJ exome AF: 0.00510

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000432

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000586

Gnomad4 OTH exome AF: 0.00249

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152236 Hom.: 1 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74446

Gnomad4 AFR AF: 0.00426

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00280

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00156 AC: 190

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00104

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PREPL: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PREPL p.Lys532Arg variant was not identified in the literature but was identified in dbSNP (ID: rs111438719) and ClinVar (classified as likely benign by Invitae and as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 433 of 280810 chromosomes (1 homozygous) at a frequency of 0.001542 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 60 of 10336 chromosomes (freq: 0.005805), Latino in 142 of 35010 chromosomes (freq: 0.004056), African in 84 of 24904 chromosomes (freq: 0.003373), Other in 18 of 7174 chromosomes (freq: 0.002509), European (non-Finnish) in 116 of 128520 chromosomes (freq: 0.000903) and South Asian in 13 of 30024 chromosomes (freq: 0.000433), but was not observed in the East Asian or European (Finnish) populations. The p.Lys532 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Myasthenic syndrome, congenital, 22 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;.;.;.;D;.;.;T;T;T
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.26	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.054	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;D;T;T;T;T;T
Polyphen		0.59, 0.18, 0.99	.;.;.;P;.;P;P;P;B;D
Vest4		0.27
MVP		0.20
MPC		0.0057
ClinPred		0.028	T
GERP RS		4.3
Varity_R		0.050
gMVP		0.44

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: rs111438719; hg19: chr2-44550435;