1-225921254-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_013328.4(PYCR2):​c.751C>A​(p.Arg251Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

PYCR2
NM_013328.4 missense

Scores

13
4
2

Clinical Significance

Not reported in ClinVar

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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 chr1-225921254-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192394.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYCR2NM_013328.4 linkc.751C>A p.Arg251Ser missense_variant Exon 6 of 7 ENST00000343818.11 NP_037460.2 Q96C36A0A0S2Z5U6
PYCR2NM_001271681.2 linkc.529C>A p.Arg177Ser missense_variant Exon 5 of 6 NP_001258610.1 Q96C36A0A087WTV6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYCR2ENST00000343818.11 linkc.751C>A p.Arg251Ser missense_variant Exon 6 of 7 1 NM_013328.4 ENSP00000342502.6 Q96C36
ENSG00000255835ENST00000432920.2 linkc.529C>A p.Arg177Ser missense_variant Exon 5 of 8 2 ENSP00000414068.2 J3KR12

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
.;T;.;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Uncertain
2.5
.;.;.;M
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-4.7
D;.;.;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
.;.;.;D
Vest4
0.80
MutPred
0.81
.;.;.;Loss of helix (P = 0.1299);
MVP
0.93
MPC
1.3
ClinPred
1.0
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.87

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.

Other links and lift over

dbSNP: rs876657403; hg19: chr1-226108954; API