19-35800150-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_021232.2(PRODH2):​c.1271G>A​(p.Arg424Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000623 in 1,605,122 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 2 hom. )

Consequence

PRODH2
NM_021232.2 missense

Scores

10
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.93
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.878
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRODH2NM_021232.2 linkc.1271G>A p.Arg424Gln missense_variant Exon 10 of 10 ENST00000653904.2 NP_067055.2
PRODH2NM_001378292.1 linkc.1115G>A p.Arg372Gln missense_variant Exon 9 of 9 NP_001365221.1
PRODH2NM_001378293.1 linkc.*48G>A 3_prime_UTR_variant Exon 9 of 9 NP_001365222.1
PRODH2NM_001378294.1 linkc.*48G>A 3_prime_UTR_variant Exon 8 of 8 NP_001365223.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRODH2ENST00000653904.2 linkc.1271G>A p.Arg424Gln missense_variant Exon 10 of 10 NM_021232.2 ENSP00000499779.1 A0A590UKC3

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000961
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000120
AC:
28
AN:
232582
Hom.:
1
AF XY:
0.0000953
AC XY:
12
AN XY:
125936
show subpopulations
Gnomad AFR exome
AF:
0.000209
Gnomad AMR exome
AF:
0.0000609
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000114
Gnomad SAS exome
AF:
0.000559
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000385
Gnomad OTH exome
AF:
0.000174
GnomAD4 exome
AF:
0.0000564
AC:
82
AN:
1452790
Hom.:
2
Cov.:
31
AF XY:
0.0000582
AC XY:
42
AN XY:
721922
show subpopulations
Gnomad4 AFR exome
AF:
0.000210
Gnomad4 AMR exome
AF:
0.0000459
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000762
Gnomad4 SAS exome
AF:
0.000342
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.000417
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152332
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000963
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.000132
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000124
AC:
15
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 19, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1499G>A (p.R500Q) alteration is located in exon 11 (coding exon 11) of the PRODH2 gene. This alteration results from a G to A substitution at nucleotide position 1499, causing the arginine (R) at amino acid position 500 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Uncertain
0.78
D
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MVP
0.76
MPC
0.66
ClinPred
0.94
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.70
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs146900274; hg19: chr19-36291052; API