2-44339365-TAGAGAGAG-TAGAGAGAGAG

Variant names:

• chr2-44339365-T-TAG
• rs750292662
• NM_001171613.2:c.486-4_486-3dupCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001171613.2(PREPL):​c.486-4_486-3dupCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,524,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: PREPL NM_001171613.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0230
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-44339365-T-TAG is Benign according to our data. Variant chr2-44339365-T-TAG is described in ClinVar as Likely_benign. ClinVar VariationId is 478320.Status of the report is criteria_provided_single_submitter, 1 stars.

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.486-4_486-3dupCT		splice_region intron	N/A	NP_001165084.1
	PREPL	NM_001171603.1		c.753-4_753-3dupCT		splice_region intron	N/A	NP_001165074.1
	PREPL	NM_001171606.2		c.753-4_753-3dupCT		splice_region intron	N/A	NP_001165077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.486-3_486-2insCT		splice_region intron	N/A	ENSP00000387095.2
	PREPL	ENST00000260648.10	TSL:1	c.753-3_753-2insCT		splice_region intron	N/A	ENSP00000260648.6
	PREPL	ENST00000409936.5	TSL:1	c.753-3_753-2insCT		splice_region intron	N/A	ENSP00000386543.1

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 47 AN: 149678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00201

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.000974

GnomAD2 exomes AF: 0.00133 AC: 168 AN: 126748 AF XY: 0.00141

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000847

Gnomad FIN exome AF: 0.00329

Gnomad NFE exome AF: 0.000823

Gnomad OTH exome AF: 0.00453

GnomAD4 exome AF: 0.000277 AC: 381 AN: 1374948 Hom.: 0 Cov.: 31 AF XY: 0.000289 AC XY: 198 AN XY: 684174

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

African (AFR) AF: 0.000318 AC: 10 AN: 31426

American (AMR) AF: 0.00123 AC: 52 AN: 42176

Ashkenazi Jewish (ASJ) AF: 0.0000408 AC: 1 AN: 24484

East Asian (EAS) AF: 0.000218 AC: 8 AN: 36676

South Asian (SAS) AF: 0.000274 AC: 22 AN: 80378

European-Finnish (FIN) AF: 0.00158 AC: 79 AN: 49874

Middle Eastern (MID) AF: 0.000374 AC: 2 AN: 5352

European-Non Finnish (NFE) AF: 0.000182 AC: 191 AN: 1048120

Other (OTH) AF: 0.000283 AC: 16 AN: 56462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000314 AC: 47 AN: 149782 Hom.: 0 Cov.: 32 AF XY: 0.000425 AC XY: 31 AN XY: 73018

African (AFR) AF: 0.000146 AC: 6 AN: 41028

American (AMR) AF: 0.000400 AC: 6 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00201 AC: 20 AN: 9948

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

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67182

Other (OTH) AF: 0.000963 AC: 2 AN: 2076

Alfa AF: 0.00260 Hom.: 0

Bravo AF: 0.000174

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Benign:1

Aug 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.023
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs750292662; hg19: chr2-44566504; COSMIC: COSV53216644; COSMIC: COSV53216644;