2-1649142-G-C

Variant names:

• chr2-1649142-G-C
• rs587777572
• NM_012293.3:c.2638C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_012293.3(PXDN):​c.2638C>G​(p.Arg880Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R880C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.57
• Publications: 4 publications found

Genes affected

PXDN (HGNC:14966): (peroxidasin) This gene encodes a heme-containing peroxidase that is secreted into the extracellular matrix. It is involved in extracellular matrix formation, and may function in the physiological and pathological fibrogenic response in fibrotic kidney. Mutations in this gene cause corneal opacification and other ocular anomalies, and also microphthalmia and anterior segment dysgenesis. [provided by RefSeq, Aug 2014]

PXDN Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-1649142-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 140742.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDN	NM_012293.3	c.2638C>G	p.Arg880Gly	missense_variant	Exon 17 of 23	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PXDN	ENST00000252804.9	c.2638C>G	p.Arg880Gly	missense_variant	Exon 17 of 23	1	NM_012293.3	ENSP00000252804.4
PXDN	ENST00000478155.5	n.2697-4390C>G		intron_variant	Intron 9 of 14	2
PXDN	ENST00000465809.1	n.*223C>G		downstream_gene_variant		4
PXDN	ENST00000493779.1	n.*101C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 86

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Gain of sheet (P = 0.0101);
MVP		0.91
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.97
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs587777572; hg19: chr2-1652914;