NM_021232.2:c.1043G>A

Variant names:

• chr19-35803037-C-T
• rs755189528
• NM_021232.2:c.1043G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_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. 15/21 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.182
• Publications: 1 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: Likely_benign. The variant received -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 VariationId is 3425592.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1043G>A	p.Arg348His	missense	Exon 8 of 10	NP_067055.2	Q9UF12
	PRODH2	NM_001378292.1		c.887G>A	p.Arg296His	missense	Exon 7 of 9	NP_001365221.1
	PRODH2	NM_001378293.1		c.1043G>A	p.Arg348His	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.1043G>A	p.Arg348His	missense	Exon 8 of 10	ENSP00000499779.1	Q9UF12
	PRODH2	ENST00000301175.7	TSL:1	c.1043G>A	p.Arg348His	missense	Exon 9 of 11	ENSP00000301175.4	Q9UF12
	PRODH2	ENST00000881789.1		c.1160G>A	p.Arg387His	missense	Exon 10 of 12	ENSP00000551848.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152146 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000931 AC: 18 AN: 193242 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000818

Gnomad AMR exome AF: 0.000107

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome 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

African (AFR) AF: 0.0000305 AC: 1 AN: 32810

American (AMR) AF: 0.000101 AC: 4 AN: 39438

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25352

East Asian (EAS) AF: 0.00 AC: 0 AN: 38020

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50942

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.0000782 AC: 85 AN: 1086316

Other (OTH) AF: 0.0000512 AC: 3 AN: 58546

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74302

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000500 AC: 6

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.18
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.031
Sift	Benign	0.34	T
Sift4G	Benign	0.18	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs755189528; hg19: chr19-36293939; COSMIC: COSV56559982; COSMIC: COSV56559982;