dbSNP rs1553360075: PREPL:p.Gln80LysfsTer16 (chr2-44346369-CTTGT-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006036.4(PREPL):c.237_240delACAA(p.Gln80LysfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PREPL
NM_006036.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.56

Publications

0 publications found

Variant links:

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

PREPL links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-44346369-CTTGT-C is Pathogenic according to our data. Variant chr2-44346369-CTTGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 478314.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PREPL	NM_001171613.2	MANE Select	c.-31_-28delACAA		5_prime_UTR	Exon 2 of 14	NP_001165084.1	Q4J6C6-4
PREPL	NM_001171603.1		c.237_240delACAA	p.Gln80LysfsTer16	frameshift	Exon 3 of 15	NP_001165074.1	Q4J6C6-1
PREPL	NM_001171606.2		c.237_240delACAA	p.Gln80LysfsTer16	frameshift	Exon 3 of 15	NP_001165077.1	Q4J6C6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PREPL	ENST00000260648.10	TSL:1	c.237_240delACAA	p.Gln80LysfsTer16	frameshift	Exon 2 of 14	ENSP00000260648.6	Q4J6C6-1
PREPL	ENST00000409936.5	TSL:1	c.237_240delACAA	p.Gln80LysfsTer16	frameshift	Exon 3 of 15	ENSP00000386543.1	Q4J6C6-1
PREPL	ENST00000378511.7	TSL:1	c.237_240delACAA	p.Gln80LysfsTer16	frameshift	Exon 2 of 13	ENSP00000367772.3	Q4J6C6-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460600

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

726620

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111500

Other (OTH)

AF:

0.00

AC:

AN:

60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myasthenic syndrome, congenital, 22 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=13/187

disease causing (fs/PTC)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over