2-44339365-TAGAGAGAG-TAGAGAG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_001171613.2(PREPL):​c.486-4_486-3delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,196,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: PREPL NM_001171613.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.456
• 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 -6 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0249) population. However there is too low homozygotes in high coverage region: (expected more than 27, got 0).
• BP6: Variant 2-44339365-TAG-T is Benign according to our data. Variant chr2-44339365-TAG-T is described in ClinVar as Benign. ClinVar VariationId is 810926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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_486-3delCT		splice_region intron	N/A	NP_001165084.1
	PREPL	NM_001171603.1		c.753-4_753-3delCT		splice_region intron	N/A	NP_001165074.1
	PREPL	NM_001171606.2		c.753-4_753-3delCT		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.486-4_486-3delCT		splice_region intron	N/A	ENSP00000387095.2
	PREPL	ENST00000260648.10	TSL:1	c.753-4_753-3delCT		splice_region intron	N/A	ENSP00000260648.6
	PREPL	ENST00000409936.5	TSL:1	c.753-4_753-3delCT		splice_region intron	N/A	ENSP00000386543.1

Frequencies

GnomAD3 genomes AF: 0.000201 AC: 30 AN: 149256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0396 AC: 5020 AN: 126748 AF XY: 0.0431

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.0455

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0242

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0109 AC: 11388 AN: 1046656 Hom.: 0 AF XY: 0.0120 AC XY: 6160 AN XY: 515390

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

African (AFR) AF: 0.00925 AC: 215 AN: 23232

American (AMR) AF: 0.0265 AC: 771 AN: 29118

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 363 AN: 17196

East Asian (EAS) AF: 0.0146 AC: 350 AN: 23964

South Asian (SAS) AF: 0.0255 AC: 1291 AN: 50592

European-Finnish (FIN) AF: 0.0192 AC: 724 AN: 37756

Middle Eastern (MID) AF: 0.0144 AC: 63 AN: 4370

European-Non Finnish (NFE) AF: 0.00866 AC: 7096 AN: 818982

Other (OTH) AF: 0.0124 AC: 515 AN: 41446

⚠️ 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: 0.000201 AC: 30 AN: 149358 Hom.: 0 Cov.: 32 AF XY: 0.000151 AC XY: 11 AN XY: 72786

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

African (AFR) AF: 0.0000732 AC: 3 AN: 40970

American (AMR) AF: 0.000200 AC: 3 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

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

European-Finnish (FIN) AF: 0.00122 AC: 12 AN: 9800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67048

Other (OTH) AF: 0.00 AC: 0 AN: 2060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0914 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myasthenic syndrome, congenital, 22 Benign:2

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs750292662; hg19: chr2-44566504; COSMIC: COSV53215724; COSMIC: COSV53215724;