rs117063721

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_013328.4(PYCR2):c.941C>T(p.Ala314Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,314,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. A314G) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PYCR2
NM_013328.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.492

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 10
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PYCR2 links:

ENSG00000255835 (HGNC:):

ENSG00000255835 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.94826 (below the threshold of 3.09). Trascript score misZ: 0.76229 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive primary microcephaly, hypomyelinating leukodystrophy 10.

BP4

Computational evidence support a benign effect (MetaRNN=0.08415386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR2	NM_013328.4 link	c.941C>T	p.Ala314Val	missense_variant	Exon 7 of 7	ENST00000343818.11	NP_037460.2	Q96C36A0A0S2Z5U6
PYCR2	NM_001271681.2 link	c.719C>T	p.Ala240Val	missense_variant	Exon 6 of 6		NP_001258610.1	Q96C36A0A087WTV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYCR2	ENST00000343818.11 link	c.941C>T	p.Ala314Val	missense_variant	Exon 7 of 7	1	NM_013328.4	ENSP00000342502.6	Q96C36
ENSG00000255835	ENST00000432920.2 link	c.575+731C>T		intron_variant	Intron 5 of 7	2		ENSP00000414068.2	J3KR12
PYCR2	ENST00000612039.4 link	c.719C>T	p.Ala240Val	missense_variant	Exon 6 of 6	3		ENSP00000478165.1	A0A087WTV6
PYCR2	ENST00000478402.5 link	n.2550C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000152

AC:

AN:

1314930

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

653488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28592

American (AMR)

AF:

0.00

AC:

AN:

33252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21252

East Asian (EAS)

AF:

0.00

AC:

AN:

38062

South Asian (SAS)

AF:

0.00

AC:

AN:

74296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5042

European-Non Finnish (NFE)

AF:

0.00000198

AC:

AN:

1008296

Other (OTH)

AF:

0.00

AC:

AN:

54994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.1

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0065

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.084

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.9

.;.;L

PhyloP100

0.49

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.25

.;.;N

REVEL

Benign

0.14

Sift

Benign

0.10

.;.;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0040

.;.;B

Vest4

0.057

MutPred

0.058

.;.;Gain of methylation at K319 (P = 0.0454);

MVP

0.83

MPC

0.30

ClinPred

0.11

GERP RS

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.017

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

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

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rs117063721

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over