rs151116193

Variant names:

• chr2-44322842-T-C
• rs151116193
• NM_001171613.2:c.1642A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001171613.2(PREPL):​c.1642A>G​(p.Ile548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,672 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PREPL NM_001171613.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.362
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01321727).
• BP6: Variant 2-44322842-T-C is Benign according to our data. Variant chr2-44322842-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 544535.

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.1642A>G	p.Ile548Val	missense	Exon 12 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.1909A>G	p.Ile637Val	missense	Exon 13 of 15	NP_001165074.1	Q4J6C6-1
	PREPL	NM_001171606.2		c.1909A>G	p.Ile637Val	missense	Exon 13 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.1642A>G	p.Ile548Val	missense	Exon 12 of 14	ENSP00000387095.2	Q4J6C6-4
	PREPL	ENST00000260648.10	TSL:1	c.1909A>G	p.Ile637Val	missense	Exon 12 of 14	ENSP00000260648.6	Q4J6C6-1
	PREPL	ENST00000409936.5	TSL:1	c.1909A>G	p.Ile637Val	missense	Exon 13 of 15	ENSP00000386543.1	Q4J6C6-1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000200 AC: 5 AN: 250402 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461352 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726986

African (AFR) AF: 0.000209 AC: 7 AN: 33438

American (AMR) AF: 0.000112 AC: 5 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111686

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74490

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

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

Alfa AF: 0.000109 Hom.: 1

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.021
DANN	Benign	0.48
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.36
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.043
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.13
MPC		0.0054
ClinPred		0.031	T
GERP RS		-8.0
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.43
Mutation Taster		=98/2	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: rs151116193; hg19: chr2-44549981;