1-17079288-A-G

Position:

• chr1-17079288-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007365.3(PADI2):​c.1286T>C​(p.Ile429Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 8.72

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PADI2	NM_007365.3	c.1286T>C	p.Ile429Thr	missense_variant	11/16	ENST00000375486.9	NP_031391.2
PADI2	XM_017000148.3	c.341T>C	p.Ile114Thr	missense_variant	3/8		XP_016855637.1
PADI2	XM_047442975.1	c.1158+3257T>C		intron_variant			XP_047298931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PADI2	ENST00000375486.9	c.1286T>C	p.Ile429Thr	missense_variant	11/16	1	NM_007365.3	ENSP00000364635.4
PADI2	ENST00000375481.1	c.1286T>C	p.Ile429Thr	missense_variant	11/11	1		ENSP00000364630.1
PADI2	ENST00000466151.1	n.913T>C		non_coding_transcript_exon_variant	3/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Apr 29, 2024

The c.1286T>C (p.I429T) alteration is located in exon 11 (coding exon 11) of the PADI2 gene. This alteration results from a T to C substitution at nucleotide position 1286, causing the isoleucine (I) at amino acid position 429 to be replaced by a threonine (T). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.85	P;.
Vest4		0.93
MutPred		0.82		Loss of stability (P = 0.0025);Loss of stability (P = 0.0025);
MVP		0.58
MPC		0.77
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.85
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1570981070; hg19: chr1-17405783;