19-12799911-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005809.6(PRDX2):c.459T>G(p.Asp153Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,613,818 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00058 (1 hom.)
• Consequence: PRDX2 NM_005809.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.41

Genes affected

PRDX2 (HGNC:9353): (peroxiredoxin 2) This gene encodes a member of the peroxiredoxin family of antioxidant enzymes, which reduce hydrogen peroxide and alkyl hydroperoxides. The encoded protein plays an antioxidant protective role in cells, and it may contribute to the antiviral activity of CD8(+) T-cells. The crystal structure of this protein has been resolved to 2.7 angstroms. This protein prevents hemolytic anemia from oxidative stress by stabilizing hemoglobin, thus making this gene a therapeutic target for patients with hemolytic anemia. This protein may have a proliferative effect and play a role in cancer development or progression. Related pseudogenes have been identified on chromosomes 5, 6, 10 and 13. [provided by RefSeq, Mar 2013]

(HGNC:):

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03010568).
• BS2: High AC in GnomAd at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDX2	NM_005809.6	c.459T>G	p.Asp153Glu	missense_variant	5/6	ENST00000301522.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDX2	ENST00000301522.3	c.459T>G	p.Asp153Glu	missense_variant	5/6	1	NM_005809.6	P1
	ENST00000585496.1	n.201-1843A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000545 AC: 137 AN: 251400 Hom.: 0 AF XY: 0.000559 AC XY: 76 AN XY: 135888

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.000739

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000575 AC: 841 AN: 1461558 Hom.: 1 Cov.: 31 AF XY: 0.000579 AC XY: 421 AN XY: 727076

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.000591

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152260 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74446

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000860 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.00136

EpiControl AF: 0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.459T>G (p.D153E) alteration is located in exon 5 (coding exon 4) of the PRDX2 gene. This alteration results from a T to G substitution at nucleotide position 459, causing the aspartic acid (D) at amino acid position 153 to be replaced by a glutamic acid (E). 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	0.29
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.33
Dann	Benign	0.93
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.029
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.51		Gain of disorder (P = 0.1981);
MVP		0.17
MPC		0.38
ClinPred		0.012	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.22

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

Other links and lift over

dbSNP: rs34012472; hg19: chr19-12910725;