19-35803070-C-A

Variant names:

• chr19-35803070-C-A
• rs553353688
• NM_021232.2:c.1010G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021232.2(PRODH2):​c.1010G>T​(p.Arg337Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,383,276 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: PRODH2 NM_021232.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH2	NM_021232.2	MANE Select	c.1010G>T	p.Arg337Leu	missense	Exon 8 of 10	NP_067055.2	Q9UF12
	PRODH2	NM_001378292.1		c.854G>T	p.Arg285Leu	missense	Exon 7 of 9	NP_001365221.1
	PRODH2	NM_001378293.1		c.1010G>T	p.Arg337Leu	missense	Exon 8 of 9	NP_001365222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH2	ENST00000653904.2	MANE Select	c.1010G>T	p.Arg337Leu	missense	Exon 8 of 10	ENSP00000499779.1	Q9UF12
	PRODH2	ENST00000301175.7	TSL:1	c.1010G>T	p.Arg337Leu	missense	Exon 9 of 11	ENSP00000301175.4	Q9UF12
	PRODH2	ENST00000881789.1		c.1127G>T	p.Arg376Leu	missense	Exon 10 of 12	ENSP00000551848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000868 AC: 12 AN: 1383276 Hom.: 0 Cov.: 30 AF XY: 0.00000738 AC XY: 5 AN XY: 677874

African (AFR) AF: 0.00 AC: 0 AN: 31916

American (AMR) AF: 0.00 AC: 0 AN: 36126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24978

East Asian (EAS) AF: 0.00 AC: 0 AN: 36188

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.0000103 AC: 11 AN: 1063862

Other (OTH) AF: 0.00 AC: 0 AN: 57154

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.94	T
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.17
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.65
MutPred		0.66		Loss of disorder (P = 0.0598)
MVP		0.50
MPC		0.64
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.52
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs553353688; hg19: chr19-36293972;