chr18-46821017-G-T

Variant names:

• chr18-46821017-G-T
• rs1472124182
• NM_004671.5:c.1564C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004671.5(PIAS2):​c.1564C>A​(p.Pro522Thr) 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. 15/22 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: PIAS2 NM_004671.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

Genes affected

PIAS2 (HGNC:17311): (protein inhibitor of activated STAT 2) This gene encodes a member of the protein inhibitor of activated STAT family, which function as SUMO E3 ligases and play important roles in many cellular processes by mediating the sumoylation of target proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Isoforms of the encoded protein enhance the sumoylation of specific target proteins including the p53 tumor suppressor protein, c-Jun, and the androgen receptor. A pseudogene of this gene is located on the short arm of chromosome 4. The symbol MIZ1 has also been associated with ZBTB17 which is a different gene located on chromosome 1. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039214283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIAS2	NM_004671.5	c.1564C>A	p.Pro522Thr	missense_variant	Exon 12 of 14	ENST00000585916.6	NP_004662.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIAS2	ENST00000585916.6	c.1564C>A	p.Pro522Thr	missense_variant	Exon 12 of 14	1	NM_004671.5	ENSP00000465676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1564C>A (p.P522T) alteration is located in exon 1 (coding exon 1) of the PIAS2 gene. This alteration results from a C to A substitution at nucleotide position 1564, causing the proline (P) at amino acid position 522 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	Benign	0.059
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Benign	0.15
DEOGEN2	Benign	0.076	T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.035	N;N;.
PhyloP100		1.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.35	.;N;N
REVEL	Benign	0.071
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.15
MutPred		0.13		Gain of glycosylation at P522 (P = 0.0254);Gain of glycosylation at P522 (P = 0.0254);.;
MVP		0.25
MPC		0.60
ClinPred		0.15	T
GERP RS		4.1
Varity_R		0.047
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1472124182; hg19: chr18-44400980;