1-225921246-CAG-CAGAG

Variant names:

• chr1-225921246-C-CAG
• rs886043378
• NM_013328.4:c.757_758dupCT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_013328.4(PYCR2):​c.757_758dupCT​(p.Leu254CysfsTer35) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYCR2 NM_013328.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.27
• Publications: 0 publications found

Genes affected

PYCR2 (HGNC:30262): (pyrroline-5-carboxylate reductase 2) This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]

PYCR2 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255835 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.213 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-225921246-C-CAG is Pathogenic according to our data. Variant chr1-225921246-C-CAG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 286401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013328.4. 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
	PYCR2	NM_013328.4	MANE Select	c.757_758dupCT	p.Leu254CysfsTer35	frameshift	Exon 6 of 7	NP_037460.2
	PYCR2	NM_001271681.2		c.535_536dupCT	p.Leu180CysfsTer35	frameshift	Exon 5 of 6	NP_001258610.1	A0A087WTV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR2	ENST00000343818.11	TSL:1 MANE Select	c.757_758dupCT	p.Leu254CysfsTer35	frameshift	Exon 6 of 7	ENSP00000342502.6	Q96C36
	ENSG00000255835	ENST00000432920.2	TSL:2	c.535_536dupCT	p.Leu180CysfsTer297	frameshift	Exon 5 of 8	ENSP00000414068.2	J3KR12
	PYCR2	ENST00000872062.1		c.754_755dupCT	p.Leu253CysfsTer35	frameshift	Exon 6 of 7	ENSP00000542121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Hypomyelinating leukodystrophy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886043378; hg19: chr1-226108946;