chr2-1635502-C-CGTGATTCAAG

Position:

• chr2-1635502-C-CGTGATTCAAG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_012293.3(PXDN):​c.4225_4226insCTTGAATCAC​(p.Arg1409ProfsTer2) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PXDN NM_012293.3 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.25

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]

LOC124907723 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0484 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-1635502-C-CGTGATTCAAG is Pathogenic according to our data. Variant chr2-1635502-C-CGTGATTCAAG is described in ClinVar as [Pathogenic]. Clinvar id is 694376.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXDN	NM_012293.3	c.4225_4226insCTTGAATCAC	p.Arg1409ProfsTer2	stop_gained, frameshift_variant	22/23	ENST00000252804.9	NP_036425.1
LOC124907723	XR_007086188.1	n.344-182_344-173dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXDN	ENST00000252804.9	c.4225_4226insCTTGAATCAC	p.Arg1409ProfsTer2	stop_gained, frameshift_variant	22/23	1	NM_012293.3	ENSP00000252804	P1
PXDN	ENST00000478155.5	n.3313_3314insCTTGAATCAC		non_coding_transcript_exon_variant	14/15	2
PXDN	ENST00000493654.1	n.1562_1563insCTTGAATCAC		non_coding_transcript_exon_variant	1/2	2
PXDN	ENST00000453308.1	c.*15_*16insCTTGAATCAC		3_prime_UTR_variant, NMD_transcript_variant	3/4	3		ENSP00000414098

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anterior segment dysgenesis 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Department, University Hospital of Toulouse

Jul 19, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1572110097; hg19: chr2-1639274;