rs773867044

Variant names:

• chr2-44323371-G-T
• rs773867044
• NM_001171613.2:c.1520C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001171613.2(PREPL):​c.1520C>A​(p.Thr507Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,606,470 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T507A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09
• 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), Illumina, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02763182).
• BP6: Variant 2-44323371-G-T is Benign according to our data. Variant chr2-44323371-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 478311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000205 (298/1454282) while in subpopulation SAS AF = 0.00242 (207/85610). AF 95% confidence interval is 0.00215. There are 1 homozygotes in GnomAdExome4. There are 200 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	NM_001171613.2	MANE Select	c.1520C>A	p.Thr507Lys	missense	Exon 11 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.1787C>A	p.Thr596Lys	missense	Exon 12 of 15	NP_001165074.1	Q4J6C6-1
	PREPL	NM_001171606.2		c.1787C>A	p.Thr596Lys	missense	Exon 12 of 15	NP_001165077.1	Q4J6C6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.1520C>A	p.Thr507Lys	missense	Exon 11 of 14	ENSP00000387095.2	Q4J6C6-4
	PREPL	ENST00000260648.10	TSL:1	c.1787C>A	p.Thr596Lys	missense	Exon 11 of 14	ENSP00000260648.6	Q4J6C6-1
	PREPL	ENST00000409936.5	TSL:1	c.1787C>A	p.Thr596Lys	missense	Exon 12 of 15	ENSP00000386543.1	Q4J6C6-1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000357 AC: 89 AN: 249448 AF XY: 0.000482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000205 AC: 298 AN: 1454282 Hom.: 1 Cov.: 31 AF XY: 0.000276 AC XY: 200 AN XY: 723750

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.0000225 AC: 1 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00242 AC: 207 AN: 85610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5748

European-Non Finnish (NFE) AF: 0.0000560 AC: 62 AN: 1106162

Other (OTH) AF: 0.000266 AC: 16 AN: 60160

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74416

African (AFR) AF: 0.0000241 AC: 1 AN: 41532

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000219

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Myasthenic syndrome, congenital, 22 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.064
Sift	Benign	0.056	T
Sift4G	Benign	0.45	T
Polyphen		0.0020	B
Vest4		0.45
MutPred		0.62		Gain of ubiquitination at T596 (P = 0.0211)
MVP		0.25
MPC		0.0062
ClinPred		0.017	T
GERP RS		2.4
PromoterAI		-0.018	Neutral
Varity_R		0.077
gMVP		0.56
Mutation Taster		=95/5	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: rs773867044; hg19: chr2-44550510;