1-225921311-A-C

Position:

• chr1-225921311-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 254250.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.694T>G	p.Cys232Gly	missense_variant	6/7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.472T>G	p.Cys158Gly	missense_variant	5/6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11	c.694T>G	p.Cys232Gly	missense_variant	6/7	1	NM_013328.4	ENSP00000342502	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypomyelinating leukodystrophy 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

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;.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.6	.;.;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.4	D;.;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D;.;.;D
Sift4G	Benign	0.070	T;T;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037933; hg19: chr1-226109011;