rs372781135

Positions:

Variant summary

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

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 Pathogenic (no stars). 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

Pathogenic no assertion criteria provided P:2

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 [Pathogenic]. Clinvar id is 192393.Status of the report is no_assertion_criteria_provided, 0 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/exons	MANE	Protein	UniProt
PYCR2	NM_013328.4 linkuse as main transcript	c.355C>T	p.Arg119Cys	missense_variant	4/7	ENST00000343818.11	NP_037460.2	Q96C36A0A0S2Z5U6
PYCR2	NM_001271681.2 linkuse as main transcript	c.318+161C>T		intron_variant			NP_001258610.1	Q96C36A0A087WTV6
MIR6741	NR_106799.1 linkuse as main transcript	n.*37C>T		downstream_gene_variant
MIR6741	unassigned_transcript_295 use as main transcript	n.*37C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11 linkuse as main transcript	c.355C>T	p.Arg119Cys	missense_variant	4/7	1	NM_013328.4	ENSP00000342502.6		Q96C36
ENSG00000255835	ENST00000432920.2 linkuse as main transcript	c.318+161C>T		intron_variant		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: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 10

Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 2015	- -

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