19-35803037-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_021232.2(PRODH2):​c.1043G>A​(p.Arg348His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,569,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

PRODH2
NM_021232.2 missense

Scores

18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.182
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 Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06623644).
BP6
Variant 19-35803037-C-T is Benign according to our data. Variant chr19-35803037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3425592.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRODH2NM_021232.2 linkc.1043G>A p.Arg348His missense_variant Exon 8 of 10 ENST00000653904.2 NP_067055.2
PRODH2NM_001378292.1 linkc.887G>A p.Arg296His missense_variant Exon 7 of 9 NP_001365221.1
PRODH2NM_001378293.1 linkc.1043G>A p.Arg348His missense_variant Exon 8 of 9 NP_001365222.1
PRODH2NM_001378294.1 linkc.887G>A p.Arg296His missense_variant Exon 7 of 8 NP_001365223.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRODH2ENST00000653904.2 linkc.1043G>A p.Arg348His missense_variant Exon 8 of 10 NM_021232.2 ENSP00000499779.1 A0A590UKC3

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152146
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000677
AC:
96
AN:
1417530
Hom.:
0
Cov.:
30
AF XY:
0.0000586
AC XY:
41
AN XY:
699988
show subpopulations
Gnomad4 AFR exome
AF:
0.0000305
Gnomad4 AMR exome
AF:
0.000101
Gnomad4 ASJ exome
AF:
0.0000394
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000124
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000782
Gnomad4 OTH exome
AF:
0.0000512
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.0000500
AC:
6

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 03, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
0.79
DANN
Benign
0.88
DEOGEN2
Benign
0.32
T;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.48
T;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.066
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-1.5
N;.
REVEL
Benign
0.031
Sift
Benign
0.34
T;.
Sift4G
Benign
0.18
T;T
Polyphen
0.031
B;.
Vest4
0.13
MVP
0.048
MPC
0.17
ClinPred
0.015
T
GERP RS
-2.1
Varity_R
0.029
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs755189528; hg19: chr19-36293939; COSMIC: COSV56559982; COSMIC: COSV56559982; API