Genetic Variant PYCR2:p.Ala314Gly (chr1-225920477-G-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_013328.4(PYCR2):c.941C>G(p.Ala314Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00063 in 1,467,138 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00080 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00061 ( 8 hom. )

Consequence

PYCR2
NM_013328.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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: Illumina, G2P, 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: Benign. The variant received -19 ACMG points.

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=0.0033650994).

BP6

Variant 1-225920477-G-C is Benign according to our data. Variant chr1-225920477-G-C is described in ClinVar as Benign. ClinVar VariationId is 730211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000802 (122/152212) while in subpopulation EAS AF = 0.0226 (117/5176). AF 95% confidence interval is 0.0193. There are 2 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013328.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR2	NM_013328.4	MANE Select	c.941C>G	p.Ala314Gly	missense	Exon 7 of 7	NP_037460.2
	PYCR2	NM_001271681.2		c.719C>G	p.Ala240Gly	missense	Exon 6 of 6	NP_001258610.1	A0A087WTV6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYCR2	ENST00000343818.11	TSL:1 MANE Select	c.941C>G	p.Ala314Gly	missense	Exon 7 of 7	ENSP00000342502.6	Q96C36
ENSG00000255835	ENST00000432920.2	TSL:2	c.575+731C>G		intron	N/A	ENSP00000414068.2	J3KR12
PYCR2	ENST00000872062.1		c.938C>G	p.Ala313Gly	missense	Exon 7 of 7	ENSP00000542121.1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0226

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00179

AC:

353

AN:

197250

AF XY:

0.00174

show subpopulations

Gnomad AFR exome

AF:

0.0000668

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000441

GnomAD4 exome

AF:

0.000610

AC:

802

AN:

1314926

Hom.:

Cov.:

AF XY:

0.000600

AC XY:

392

AN XY:

653484

show subpopulations

African (AFR)

AF:

0.000140

AC:

AN:

28592

American (AMR)

AF:

0.00

AC:

AN:

33252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21252

East Asian (EAS)

AF:

0.0195

AC:

743

AN:

38058

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:

0.00000298

AC:

AN:

1008296

Other (OTH)

AF:

0.000946

AC:

AN:

54994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152212

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0226

AC:

117

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000601

Hom.:

Bravo

AF:

0.00101

ExAC

AF:

0.00149

AC:

181

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

4.3

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0063

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.9

PhyloP100

0.49

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.17

REVEL

Benign

0.18

Sift

Uncertain

0.023

Sift4G

Benign

0.14

Polyphen

0.55

Vest4

0.069

MVP

0.89

MPC

0.30

ClinPred

0.018

GERP RS

-0.23

Varity_R

0.029

gMVP

0.16

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over