chr2-1648953-G-A

Variant names:

• chr2-1648953-G-A
• rs200127189
• NM_012293.3:c.2827C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_012293.3(PXDN):​c.2827C>T​(p.Arg943Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,606,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R943Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PXDN NM_012293.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.26
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026949733).
• BP6: Variant 2-1648953-G-A is Benign according to our data. Variant chr2-1648953-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471914.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00144 (219/152194) while in subpopulation AFR AF = 0.00479 (199/41536). AF 95% confidence interval is 0.00425. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDN	NM_012293.3	MANE Select	c.2827C>T	p.Arg943Trp	missense	Exon 17 of 23	NP_036425.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXDN	ENST00000252804.9	TSL:1 MANE Select	c.2827C>T	p.Arg943Trp	missense	Exon 17 of 23	ENSP00000252804.4
	PXDN	ENST00000857505.1		c.2755C>T	p.Arg919Trp	missense	Exon 16 of 22	ENSP00000527564.1
	PXDN	ENST00000478155.5	TSL:2	n.2697-4201C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000350 AC: 82 AN: 234472 AF XY: 0.000317

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.000353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000958

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1454344 Hom.: 0 Cov.: 72 AF XY: 0.000127 AC XY: 92 AN XY: 722684

African (AFR) AF: 0.00507 AC: 169 AN: 33342

American (AMR) AF: 0.000382 AC: 17 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50570

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5740

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108732

Other (OTH) AF: 0.000333 AC: 20 AN: 60010

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74414

African (AFR) AF: 0.00479 AC: 199 AN: 41536

American (AMR) AF: 0.000849 AC: 13 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.00171

ESP6500AA AF: 0.00521 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 47

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Anterior segment dysgenesis 7 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	PXDN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.0050
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.62
MPC		1.2
ClinPred		0.023	T
GERP RS		-0.90
Varity_R		0.48
gMVP		0.73
Mutation Taster		=59/41	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: rs200127189; hg19: chr2-1652725; COSMIC: COSV99415577; COSMIC: COSV99415577;