2-44322828-T-G

Variant names:

• chr2-44322828-T-G
• rs74395208
• NM_001171613.2:c.1656A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001171613.2(PREPL):​c.1656A>C​(p.Ala552Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A552A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PREPL NM_001171613.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.66
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.

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.1656A>C	p.Ala552Ala	synonymous	Exon 12 of 14	NP_001165084.1
	PREPL	NM_001171603.1		c.1923A>C	p.Ala641Ala	synonymous	Exon 13 of 15	NP_001165074.1
	PREPL	NM_001171606.2		c.1923A>C	p.Ala641Ala	synonymous	Exon 13 of 15	NP_001165077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREPL	ENST00000409411.6	TSL:1 MANE Select	c.1656A>C	p.Ala552Ala	synonymous	Exon 12 of 14	ENSP00000387095.2
	PREPL	ENST00000260648.10	TSL:1	c.1923A>C	p.Ala641Ala	synonymous	Exon 12 of 14	ENSP00000260648.6
	PREPL	ENST00000409936.5	TSL:1	c.1923A>C	p.Ala641Ala	synonymous	Exon 13 of 15	ENSP00000386543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.14
DANN	Benign	0.73
PhyloP100		-2.7
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs74395208; hg19: chr2-44549967;