2-44323293-C-G

Variant names:

• chr2-44323293-C-G
• rs375292548
• NM_001171613.2:c.1598G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001171613.2(PREPL):​c.1598G>C​(p.Arg533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R533L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.778
• Publications: 0 publications found

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]

PREPL Gene-Disease associations (from GenCC):

• hypotonia-cystinuria syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• myasthenic syndrome, congenital, 22

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1240029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREPL	NM_001171613.2	c.1598G>C	p.Arg533Pro	missense_variant	Exon 11 of 14	ENST00000409411.6	NP_001165084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREPL	ENST00000409411.6	c.1598G>C	p.Arg533Pro	missense_variant	Exon 11 of 14	1	NM_001171613.2	ENSP00000387095.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454366 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00 AC: 0 AN: 85376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106996

Other (OTH) AF: 0.00 AC: 0 AN: 60140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	.;.;.;T;T;T;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;.;.;.;D;.;.;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;.;.;L;.;L;L;L;.;.
PhyloP100		0.78
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.61	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T
Polyphen		0.051, 0.14, 0.11	.;.;.;B;.;B;B;B;B;B
Vest4		0.67
MutPred		0.45		.;.;.;Gain of ubiquitination at K621 (P = 0.038);.;Gain of ubiquitination at K621 (P = 0.038);Gain of ubiquitination at K621 (P = 0.038);Gain of ubiquitination at K621 (P = 0.038);.;.;
MVP		0.33
MPC		0.0057
ClinPred		0.42	T
GERP RS		2.6
PromoterAI		-0.0052	Neutral
Varity_R		0.16
gMVP		0.78
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs375292548; hg19: chr2-44550432;