19-35800132-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021232.2(PRODH2):​c.1289G>A​(p.Arg430Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,455,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. R430L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PRODH2
NM_021232.2 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.883
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18570384).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRODH2NM_021232.2 linkc.1289G>A p.Arg430Gln missense_variant Exon 10 of 10 ENST00000653904.2 NP_067055.2
PRODH2NM_001378292.1 linkc.1133G>A p.Arg378Gln missense_variant Exon 9 of 9 NP_001365221.1
PRODH2NM_001378293.1 linkc.*66G>A 3_prime_UTR_variant Exon 9 of 9 NP_001365222.1
PRODH2NM_001378294.1 linkc.*66G>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.1289G>A p.Arg430Gln missense_variant Exon 10 of 10 NM_021232.2 ENSP00000499779.1 A0A590UKC3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000126
AC:
3
AN:
237794
Hom.:
0
AF XY:
0.0000155
AC XY:
2
AN XY:
128840
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000561
Gnomad SAS exome
AF:
0.0000344
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000936
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000481
AC:
7
AN:
1455860
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
723666
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000235
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000361
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 16, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1517G>A (p.R506Q) 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 1517, causing the arginine (R) at amino acid position 506 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
0.072
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.052
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.044
Sift
Benign
0.12
T
Sift4G
Benign
0.17
T
Polyphen
0.39
B
Vest4
0.11
MutPred
0.53
Loss of MoRF binding (P = 0.0286);
MVP
0.21
MPC
0.19
ClinPred
0.32
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.093
gMVP
0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759488879; hg19: chr19-36291034; API