2-44343869-A-T

Variant names:

• chr2-44343869-A-T
• rs72875319
• NM_001171613.2:c.225T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001171613.2(PREPL):​c.225T>A​(p.Ala75Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,614,034 control chromosomes in the GnomAD database, including 490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (254 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (236 hom.)
• Consequence: PREPL NM_001171613.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-44343869-A-T is Benign according to our data. Variant chr2-44343869-A-T is described in ClinVar as Benign. ClinVar VariationId is 478318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

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.225T>A	p.Ala75Ala	synonymous	Exon 4 of 14	NP_001165084.1
	PREPL	NM_001171603.1		c.492T>A	p.Ala164Ala	synonymous	Exon 5 of 15	NP_001165074.1
	PREPL	NM_001171606.2		c.492T>A	p.Ala164Ala	synonymous	Exon 5 of 15	NP_001165077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.225T>A	p.Ala75Ala	synonymous	Exon 4 of 14	ENSP00000387095.2
	PREPL	ENST00000260648.10	TSL:1	c.492T>A	p.Ala164Ala	synonymous	Exon 4 of 14	ENSP00000260648.6
	PREPL	ENST00000409936.5	TSL:1	c.492T>A	p.Ala164Ala	synonymous	Exon 5 of 15	ENSP00000386543.1

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4905 AN: 152142 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.00850 AC: 2135 AN: 251160 AF XY: 0.00602

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00322 AC: 4711 AN: 1461774 Hom.: 236 Cov.: 32 AF XY: 0.00270 AC XY: 1963 AN XY: 727190

African (AFR) AF: 0.113 AC: 3777 AN: 33478

American (AMR) AF: 0.00619 AC: 277 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53416

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000183 AC: 204 AN: 1111936

Other (OTH) AF: 0.00689 AC: 416 AN: 60390

GnomAD4 genome AF: 0.0323 AC: 4911 AN: 152260 Hom.: 254 Cov.: 33 AF XY: 0.0311 AC XY: 2316 AN XY: 74452

African (AFR) AF: 0.111 AC: 4596 AN: 41524

American (AMR) AF: 0.0147 AC: 224 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68020

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0104 Hom.: 21

Bravo AF: 0.0371

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Myasthenic syndrome, congenital, 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.2
DANN	Benign	0.70
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs72875319; hg19: chr2-44571008;