Genetic Variant PADI2:p.Thr527Ala (chr1-17071462-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007365.3(PADI2):c.1579A>G(p.Thr527Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T527S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

PADI2
NM_007365.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

Publications

0 publications found

Variant links:

Genes affected

PADI2 (HGNC:18341): (peptidyl arginine deiminase 2) This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. The type II enzyme is the most widely expressed family member. Known substrates for this enzyme include myelin basic protein in the central nervous system and vimentin in skeletal muscle and macrophages. This enzyme is thought to play a role in the onset and progression of neurodegenerative human disorders, including Alzheimer disease and multiple sclerosis, and it has also been implicated in glaucoma pathogenesis. This gene exists in a cluster with four other paralogous genes. [provided by RefSeq, Jul 2008]

PADI2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PADI2	NM_007365.3 link	c.1579A>G	p.Thr527Ala	missense_variant	Exon 14 of 16	ENST00000375486.9	NP_031391.2	Q9Y2J8-1
PADI2	XM_017000148.3 link	c.634A>G	p.Thr212Ala	missense_variant	Exon 6 of 8		XP_016855637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PADI2	ENST00000375486.9 link	c.1579A>G	p.Thr527Ala	missense_variant	Exon 14 of 16	1	NM_007365.3	ENSP00000364635.4	Q9Y2J8-1
PADI2	ENST00000466151.1 link	n.1935A>G		non_coding_transcript_exon_variant	Exon 5 of 7	2
PADI2	ENST00000479534.5 link	n.526A>G		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.70

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

4.4

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.9

REVEL

Benign

0.13

Sift

Benign

0.033

Sift4G

Benign

0.27

Polyphen

0.29

Vest4

0.80

MutPred

0.49

Loss of sheet (P = 0.0315);

MVP

0.55

MPC

0.35

ClinPred

0.86

GERP RS

5.2

Varity_R

0.40

gMVP

0.81

Mutation Taster

=38/62

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over