rs372781135

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_013328.4(PYCR2):c.355C>T(p.Arg119Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PYCR2
NM_013328.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 4.99

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:

ENSG00000255835 (HGNC:):

ENSG00000255835 links:

MIR6741 (HGNC:50004): (microRNA 6741) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6741 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a strand (size 4) 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 chr1-225922042-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 1-225922043-G-A is Pathogenic according to our data. Variant chr1-225922043-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192393.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-225922043-G-A is described in Lovd as [Pathogenic]. Variant chr1-225922043-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4 link	c.355C>T	p.Arg119Cys	missense_variant	Exon 4 of 7	ENST00000343818.11	NP_037460.2	Q96C36A0A0S2Z5U6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11 link	c.355C>T	p.Arg119Cys	missense_variant	Exon 4 of 7	1	NM_013328.4	ENSP00000342502.6		Q96C36
ENSG00000255835	ENST00000432920.2 link	c.318+161C>T		intron_variant	Intron 3 of 7	2		ENSP00000414068.2		J3KR12

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251092

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 10

Pathogenic:2

May 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 12, 2024

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided

Pathogenic:1

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 119 of the PYCR2 protein (p.Arg119Cys). This variant is present in population databases (rs372781135, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of PYCR2-related conditions (PMID: 25865492, 30125339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 192393). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PYCR2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PYCR2 function (PMID: 25865492, 33771508, 36548190). This variant disrupts the p.Arg119 amino acid residue in PYCR2. Other variant(s) that disrupt this residue have been observed in individuals with PYCR2-related conditions (PMID: 34055512), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;D;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.089

MutationAssessor

Pathogenic

3.9

.;H;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.8

.;D;.;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Pathogenic

0.0

D;D;.;D

Polyphen

1.0

.;D;.;.

Vest4

0.98

MVP

0.90

MPC

1.2

ClinPred

1.0

GERP RS

3.8

Varity_R

0.96

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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