1-225921311-A-C

Variant names:

• chr1-225921311-A-C
• rs886037933
• NM_013328.4:c.694T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_013328.4(PYCR2):​c.694T>G​(p.Cys232Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYCR2 NM_013328.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.25
• Publications: 3 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: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255835 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.94826 (below the threshold of 3.09). Trascript score misZ: 0.76229 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive primary microcephaly, hypomyelinating leukodystrophy 10.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 1-225921311-A-C is Pathogenic according to our data. Variant chr1-225921311-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 254250.Status of the report is no_assertion_criteria_provided, 0 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.694T>G	p.Cys232Gly	missense	Exon 6 of 7	NP_037460.2
	PYCR2	NM_001271681.2		c.472T>G	p.Cys158Gly	missense	Exon 5 of 6	NP_001258610.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR2	ENST00000343818.11	TSL:1 MANE Select	c.694T>G	p.Cys232Gly	missense	Exon 6 of 7	ENSP00000342502.6
	ENSG00000255835	ENST00000432920.2	TSL:2	c.472T>G	p.Cys158Gly	missense	Exon 5 of 8	ENSP00000414068.2
	PYCR2	ENST00000872062.1		c.691T>G	p.Cys231Gly	missense	Exon 6 of 7	ENSP00000542121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypomyelinating leukodystrophy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.070	T
Polyphen		0.024	B
Vest4		0.94
MutPred		0.81		Gain of disorder (P = 0.005)
MVP		0.89
MPC		0.57
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.89
Mutation Taster		=30/70	disease causing (ClinVar)

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: rs886037933; hg19: chr1-226109011;