2-1648590-C-G

Variant names:

• chr2-1648590-C-G
• rs202132697
• NM_012293.3:c.3190G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012293.3(PXDN):​c.3190G>C​(p.Ala1064Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1064T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77
• Publications: 0 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012293.3. 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
	PXDN	NM_012293.3	MANE Select	c.3190G>C	p.Ala1064Pro	missense	Exon 17 of 23	NP_036425.1	Q92626-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDN	ENST00000252804.9	TSL:1 MANE Select	c.3190G>C	p.Ala1064Pro	missense	Exon 17 of 23	ENSP00000252804.4	Q92626-1
	PXDN	ENST00000857505.1		c.3118G>C	p.Ala1040Pro	missense	Exon 16 of 22	ENSP00000527564.1
	PXDN	ENST00000478155.5	TSL:2	n.2697-3838G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.11	T
Sift4G	Benign	0.098	T
Polyphen		0.98	D
Vest4		0.75
MutPred		0.65		Loss of stability (P = 0.0443)
MVP		0.88
MPC		1.4
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.97
Mutation Taster		=46/54	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: rs202132697; hg19: chr2-1652362;