NM_001171613.2:c.1598G>A

Variant names:

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

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>A​(p.Arg533His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,606,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.07341689).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171613.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	NM_001171613.2	MANE Select	c.1598G>A	p.Arg533His	missense	Exon 11 of 14	NP_001165084.1
	PREPL	NM_001171603.1		c.1865G>A	p.Arg622His	missense	Exon 12 of 15	NP_001165074.1
	PREPL	NM_001171606.2		c.1865G>A	p.Arg622His	missense	Exon 12 of 15	NP_001165077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.1598G>A	p.Arg533His	missense	Exon 11 of 14	ENSP00000387095.2
	PREPL	ENST00000260648.10	TSL:1	c.1865G>A	p.Arg622His	missense	Exon 11 of 14	ENSP00000260648.6
	PREPL	ENST00000409936.5	TSL:1	c.1865G>A	p.Arg622His	missense	Exon 12 of 15	ENSP00000386543.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151876 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248420 AF XY: 0.0000223

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1454366 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 723720

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

American (AMR) AF: 0.0000453 AC: 2 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: 0.000105 AC: 9 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: 0.00000271 AC: 3 AN: 1106996

Other (OTH) AF: 0.0000831 AC: 5 AN: 60140

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151876 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74162

African (AFR) AF: 0.0000484 AC: 2 AN: 41338

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Myasthenic syndrome, congenital, 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.78
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.036
Sift	Benign	0.23	T
Sift4G	Benign	0.13	T
Polyphen		0.0050	B
Vest4		0.24
MutPred		0.52		Gain of ubiquitination at K621 (P = 0.0434)
MVP		0.17
MPC		0.0046
ClinPred		0.11	T
GERP RS		2.6
PromoterAI		-0.015	Neutral
Varity_R		0.023
gMVP		0.45
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs375292548; hg19: chr2-44550432; COSMIC: COSV108073796; COSMIC: COSV108073796;