19-35803070-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021232.2(PRODH2):c.1010G>A(p.Arg337His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000697 in 1,535,500 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

PRODH2
NM_021232.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Publications

1 publications found

Variant links:

Genes affected

PRODH2 (HGNC:17325): (proline dehydrogenase 2) The protein encoded by this gene catalyzes the first step in the catabolism of trans-4-hydroxy-L-proline, an amino acid derivative obtained through food intake and collagen turnover. One of the downstream products of this catabolism is glyoxylate, which in people with disorders of glyoxalate metabolism can lead to an increase in oxalate levels and the formation of calcium-oxalate kidney stones. Therefore, this gene may serve as a therapeutic target against primary hyperoxalurias (PH). This gene is similar to proline dehydrogenase (oxidase) 1, a mitochondrial enzyme that catalyzes the first step in proline catabolism. [provided by RefSeq, Jan 2017]

PRODH2 Gene-Disease associations (from GenCC):

hydroxyprolinemia
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PRODH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.100635886).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021232.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH2	NM_021232.2	MANE Select	c.1010G>A	p.Arg337His	missense	Exon 8 of 10	NP_067055.2	Q9UF12
PRODH2	NM_001378292.1		c.854G>A	p.Arg285His	missense	Exon 7 of 9	NP_001365221.1
PRODH2	NM_001378293.1		c.1010G>A	p.Arg337His	missense	Exon 8 of 9	NP_001365222.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH2	ENST00000653904.2	MANE Select	c.1010G>A	p.Arg337His	missense	Exon 8 of 10	ENSP00000499779.1	Q9UF12
PRODH2	ENST00000301175.7	TSL:1	c.1010G>A	p.Arg337His	missense	Exon 9 of 11	ENSP00000301175.4	Q9UF12
PRODH2	ENST00000881789.1		c.1127G>A	p.Arg376His	missense	Exon 10 of 12	ENSP00000551848.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000169

AC:

AN:

165456

AF XY:

0.000251

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000701

AC:

AN:

1383270

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

677874

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31916

American (AMR)

AF:

0.00

AC:

AN:

36126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24978

East Asian (EAS)

AF:

0.0000553

AC:

AN:

36188

South Asian (SAS)

AF:

0.00112

AC:

AN:

77792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1063860

Other (OTH)

AF:

0.0000700

AC:

AN:

57154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000682

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000121

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.75

M_CAP

Benign

0.013

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.77

PhyloP100

2.0

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.27

Sift

Uncertain

0.015

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.22

MutPred

0.67

Loss of MoRF binding (P = 0.0978)

MVP

0.57

MPC

0.25

ClinPred

0.23

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.36

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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