1-17070118-G-T

Position:

• chr1-17070118-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007365.3(PADI2):​c.1734C>A​(p.Asp578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PADI2 NM_007365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038897604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI2	NM_007365.3	c.1734C>A	p.Asp578Glu	missense_variant	15/16	ENST00000375486.9	NP_031391.2
PADI2	XM_017000148.3	c.789C>A	p.Asp263Glu	missense_variant	7/8		XP_016855637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI2	ENST00000375486.9	c.1734C>A	p.Asp578Glu	missense_variant	15/16	1	NM_007365.3	ENSP00000364635.4
PADI2	ENST00000466151.1	n.2090C>A		non_coding_transcript_exon_variant	6/7	2
PADI2	ENST00000479534.5	n.681C>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.1734C>A (p.D578E) alteration is located in exon 15 (coding exon 15) of the PADI2 gene. This alteration results from a C to A substitution at nucleotide position 1734, causing the aspartic acid (D) at amino acid position 578 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.9
DANN	Benign	0.23
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.26	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.26		Loss of ubiquitination at K574 (P = 0.1453);
MVP		0.11
MPC		0.18
ClinPred		0.052	T
GERP RS		0.28
Varity_R		0.19
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs2078254637; hg19: chr1-17396613;