rs113272276

Variant names:

• chr2-44339162-T-C
• rs113272276
• NM_001171613.2:c.687A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_001171613.2(PREPL):​c.687A>G​(p.Glu229Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,910 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: PREPL NM_001171613.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.651
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-44339162-T-C is Benign according to our data. Variant chr2-44339162-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.651 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00215 (327/152256) while in subpopulation AMR AF = 0.00451 (69/15292). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.687A>G	p.Glu229Glu	synonymous	Exon 6 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.954A>G	p.Glu318Glu	synonymous	Exon 7 of 15	NP_001165074.1	Q4J6C6-1
	PREPL	NM_001171606.2		c.954A>G	p.Glu318Glu	synonymous	Exon 7 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.687A>G	p.Glu229Glu	synonymous	Exon 6 of 14	ENSP00000387095.2	Q4J6C6-4
	PREPL	ENST00000260648.10	TSL:1	c.954A>G	p.Glu318Glu	synonymous	Exon 6 of 14	ENSP00000260648.6	Q4J6C6-1
	PREPL	ENST00000409936.5	TSL:1	c.954A>G	p.Glu318Glu	synonymous	Exon 7 of 15	ENSP00000386543.1	Q4J6C6-1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00152 AC: 382 AN: 251098 AF XY: 0.00141

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00371

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.000915 AC: 1337 AN: 1461654 Hom.: 2 Cov.: 31 AF XY: 0.000897 AC XY: 652 AN XY: 727106

African (AFR) AF: 0.00484 AC: 162 AN: 33472

American (AMR) AF: 0.00356 AC: 159 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 133 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5764

European-Non Finnish (NFE) AF: 0.000584 AC: 649 AN: 1111864

Other (OTH) AF: 0.00273 AC: 165 AN: 60388

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74442

African (AFR) AF: 0.00428 AC: 178 AN: 41544

American (AMR) AF: 0.00451 AC: 69 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68012

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00267

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Myasthenic syndrome, congenital, 22 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.5
DANN	Benign	0.55
PhyloP100		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs113272276; hg19: chr2-44566301;