chr2-1654394-C-T

Variant names:

• chr2-1654394-C-T
• rs73178792
• NM_012293.3:c.1946+6G>A

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.1946+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,606,026 control chromosomes in the GnomAD database, including 1,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (656 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (604 hom.)
• Consequence: PXDN NM_012293.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003743
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.723
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-1654394-C-T is Benign according to our data. Variant chr2-1654394-C-T is described in ClinVar as Benign. ClinVar VariationId is 260221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

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.1946+6G>A		splice_region intron	N/A	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.1946+6G>A		splice_region intron	N/A	ENSP00000252804.4	Q92626-1
	PXDN	ENST00000433670.5	TSL:1	c.1931+6G>A		splice_region intron	N/A	ENSP00000402738.1	H7C1W1
	PXDN	ENST00000857505.1		c.1874+6G>A		splice_region intron	N/A	ENSP00000527564.1

Frequencies

GnomAD3 genomes AF: 0.0536 AC: 8151 AN: 152142 Hom.: 656 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00788

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0149 AC: 3714 AN: 249004 AF XY: 0.0114

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00995

Gnomad EAS exome AF: 0.00607

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000930

Gnomad OTH exome AF: 0.00976

GnomAD4 exome AF: 0.00629 AC: 9150 AN: 1453766 Hom.: 604 Cov.: 30 AF XY: 0.00550 AC XY: 3982 AN XY: 723414

African (AFR) AF: 0.186 AC: 6213 AN: 33316

American (AMR) AF: 0.0118 AC: 527 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 304 AN: 26082

East Asian (EAS) AF: 0.00232 AC: 92 AN: 39624

South Asian (SAS) AF: 0.00432 AC: 372 AN: 86044

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53394

Middle Eastern (MID) AF: 0.0148 AC: 85 AN: 5748

European-Non Finnish (NFE) AF: 0.000624 AC: 689 AN: 1104786

Other (OTH) AF: 0.0143 AC: 861 AN: 60116

GnomAD4 genome AF: 0.0537 AC: 8170 AN: 152260 Hom.: 656 Cov.: 33 AF XY: 0.0515 AC XY: 3832 AN XY: 74440

African (AFR) AF: 0.182 AC: 7560 AN: 41526

American (AMR) AF: 0.0207 AC: 317 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.00790 AC: 41 AN: 5188

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68030

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0253 Hom.: 204

Bravo AF: 0.0606

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00172

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.86
DANN	Benign	0.68
PhyloP100		-0.72
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.062
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: rs73178792; hg19: chr2-1658166; COSMIC: COSV53242667; COSMIC: COSV53242667;