rs76057922

Variant names:

• chr2-1666323-A-G
• rs76057922
• NM_012293.3:c.1182T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012293.3(PXDN):​c.1182T>C​(p.Ser394Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,068 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (36 hom.)
• Consequence: PXDN NM_012293.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.853
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.016).
• BP6: Variant 2-1666323-A-G is Benign according to our data. Variant chr2-1666323-A-G is described in ClinVar as Benign. ClinVar VariationId is 471911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.853 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1985/152356) while in subpopulation AFR AF = 0.0448 (1864/41592). AF 95% confidence interval is 0.0431. There are 52 homozygotes in GnomAd4. There are 973 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AR gene

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.1182T>C	p.Ser394Ser	synonymous	Exon 10 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.1182T>C	p.Ser394Ser	synonymous	Exon 10 of 23	ENSP00000252804.4	Q92626-1
	PXDN	ENST00000433670.5	TSL:1	c.1167T>C	p.Ser389Ser	synonymous	Exon 10 of 16	ENSP00000402738.1	H7C1W1
	PXDN	ENST00000857505.1		c.1110T>C	p.Ser370Ser	synonymous	Exon 9 of 22	ENSP00000527564.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1972 AN: 152238 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00340 AC: 842 AN: 247978 AF XY: 0.00274

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00150 AC: 2193 AN: 1461712 Hom.: 36 Cov.: 31 AF XY: 0.00131 AC XY: 952 AN XY: 727138

African (AFR) AF: 0.0484 AC: 1619 AN: 33480

American (AMR) AF: 0.00331 AC: 148 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000168 AC: 187 AN: 1111870

Other (OTH) AF: 0.00323 AC: 195 AN: 60374

GnomAD4 genome AF: 0.0130 AC: 1985 AN: 152356 Hom.: 52 Cov.: 33 AF XY: 0.0131 AC XY: 973 AN XY: 74506

African (AFR) AF: 0.0448 AC: 1864 AN: 41592

American (AMR) AF: 0.00438 AC: 67 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68034

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00631 Hom.: 19

Bravo AF: 0.0146

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Anterior segment dysgenesis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.079
DANN	Benign	0.28
PhyloP100		-0.85
Mutation Taster		=97/3	polymorphism

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: rs76057922; hg19: chr2-1670095;