2-44359497-C-G

Variant names:

• chr2-44359497-C-G
• rs199854790
• ENST00000260648.10:c.219G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006036.4(PREPL):​c.219G>C​(p.Lys73Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K73E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PREPL NM_006036.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48
• Publications: 1 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006036.4. 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.-49+1883G>C		intron	N/A	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.219G>C	p.Lys73Asn	missense splice_region	Exon 2 of 15	NP_001165074.1	Q4J6C6-1
	PREPL	NM_001171606.2		c.219G>C	p.Lys73Asn	missense splice_region	Exon 2 of 15	NP_001165077.1	Q4J6C6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000260648.10	TSL:1	c.219G>C	p.Lys73Asn	missense splice_region	Exon 1 of 14	ENSP00000260648.6	Q4J6C6-1
	PREPL	ENST00000409936.5	TSL:1	c.219G>C	p.Lys73Asn	missense splice_region	Exon 2 of 15	ENSP00000386543.1	Q4J6C6-1
	PREPL	ENST00000378511.7	TSL:1	c.219G>C	p.Lys73Asn	missense splice_region	Exon 1 of 13	ENSP00000367772.3	Q4J6C6-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.10
Sift	Uncertain	0.010	D
Sift4G	Benign	0.086	T
Polyphen		0.20	B
Vest4		0.60
MutPred		0.57		Loss of methylation at K73 (P = 2e-04)
MVP		0.45
MPC		0.0058
ClinPred		0.54	D
GERP RS		5.3
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.47
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.60		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199854790; hg19: chr2-44586636;