rs876657403

chr1-225921254-G-Achr1-225921254-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_013328.4(PYCR2):c.751C>T(p.Arg251Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PYCR2 NM_013328.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.95

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 19) in uniprot entity P5CR2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_013328.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-225921253-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 992853.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 1-225921254-G-A is Pathogenic according to our data. Variant chr1-225921254-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192394.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-225921254-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYCR2	NM_013328.4	c.751C>T	p.Arg251Cys	missense_variant	6/7	ENST00000343818.11
PYCR2	NM_001271681.2	c.529C>T	p.Arg177Cys	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYCR2	ENST00000343818.11	c.751C>T	p.Arg251Cys	missense_variant	6/7	1	NM_013328.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

May 07, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.1	D;.;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.91
MutPred		0.84		.;.;.;Loss of helix (P = 0.1299);
MVP		0.93
MPC		1.4
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.84

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: rs876657403; hg19: chr1-226108954;