Variant chr1-225921254-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The ENST00000343818.11(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. 12/21 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
ENST00000343818.11 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.95

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 ENST00000343818.11

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	Protein	UniProt
PYCR2	NM_013328.4 linkuse as main transcript	c.751C>T	p.Arg251Cys	missense_variant	6/7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2 linkuse as main transcript	c.529C>T	p.Arg177Cys	missense_variant	5/6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11 linkuse as main transcript	c.751C>T	p.Arg251Cys	missense_variant	6/7	1	NM_013328.4	ENSP00000342502	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727198

show subpopulations

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.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

.;T;.;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.2

.;.;.;H

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over