chr2-1648953-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
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).
Frequency
Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
PXDN
NM_012293.3 missense
NM_012293.3 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 1.26
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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 id is 471914.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PXDN | NM_012293.3 | c.2827C>T | p.Arg943Trp | missense_variant | 17/23 | ENST00000252804.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PXDN | ENST00000252804.9 | c.2827C>T | p.Arg943Trp | missense_variant | 17/23 | 1 | NM_012293.3 | P1 | |
PXDN | ENST00000478155.5 | n.2697-4201C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.00143 AC: 218AN: 152078Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000350 AC: 82AN: 234472Hom.: 0 AF XY: 0.000317 AC XY: 41AN XY: 129206
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GnomAD4 exome AF: 0.000147 AC: 214AN: 1454344Hom.: 0 Cov.: 72 AF XY: 0.000127 AC XY: 92AN XY: 722684
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GnomAD4 genome AF: 0.00144 AC: 219AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.00145 AC XY: 108AN XY: 74414
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2022 | The c.2827C>T (p.R943W) alteration is located in exon 17 (coding exon 17) of the PXDN gene. This alteration results from a C to T substitution at nucleotide position 2827, causing the arginine (R) at amino acid position 943 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
PXDN-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 15, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Anterior segment dysgenesis 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at