2-1635350-T-C

Variant names:

• chr2-1635350-T-C
• rs2241457
• NM_012293.3:c.4320+58A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012293.3(PXDN):​c.4320+58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,449,746 control chromosomes in the GnomAD database, including 50,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5393 hom., cov: 33)
  • Exomes 𝑓: 0.26 (44741 hom.)
• Consequence: PXDN NM_012293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.872
• Publications: 7 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)

LOC124907723 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-1635350-T-C is Benign according to our data. Variant chr2-1635350-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDN	NM_012293.3	c.4320+58A>G		intron_variant	Intron 22 of 22	ENST00000252804.9	NP_036425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PXDN	ENST00000252804.9	c.4320+58A>G		intron_variant	Intron 22 of 22	1	NM_012293.3	ENSP00000252804.4
PXDN	ENST00000453308.1	n.*110+58A>G		intron_variant	Intron 3 of 3	3		ENSP00000414098.1
PXDN	ENST00000478155.5	n.3408+58A>G		intron_variant	Intron 14 of 14	2
PXDN	ENST00000493654.1	n.1657+58A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39431 AN: 152060 Hom.: 5376 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.256 AC: 332527 AN: 1297568 Hom.: 44741 AF XY: 0.259 AC XY: 167224 AN XY: 645412

African (AFR) AF: 0.234 AC: 6873 AN: 29392

American (AMR) AF: 0.422 AC: 15003 AN: 35558

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7498 AN: 24548

East Asian (EAS) AF: 0.405 AC: 14239 AN: 35194

South Asian (SAS) AF: 0.362 AC: 27855 AN: 76982

European-Finnish (FIN) AF: 0.228 AC: 11221 AN: 49120

Middle Eastern (MID) AF: 0.232 AC: 926 AN: 3998

European-Non Finnish (NFE) AF: 0.237 AC: 234542 AN: 988182

Other (OTH) AF: 0.263 AC: 14370 AN: 54594

GnomAD4 genome AF: 0.259 AC: 39485 AN: 152178 Hom.: 5393 Cov.: 33 AF XY: 0.266 AC XY: 19802 AN XY: 74388

African (AFR) AF: 0.238 AC: 9894 AN: 41526

American (AMR) AF: 0.364 AC: 5576 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1057 AN: 3468

East Asian (EAS) AF: 0.398 AC: 2045 AN: 5138

South Asian (SAS) AF: 0.369 AC: 1781 AN: 4822

European-Finnish (FIN) AF: 0.239 AC: 2535 AN: 10604

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15784 AN: 68000

Other (OTH) AF: 0.254 AC: 537 AN: 2116

Alfa AF: 0.225 Hom.: 2206

Bravo AF: 0.267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

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: rs2241457; hg19: chr2-1639122; COSMIC: COSV53249460;