16-283321-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006849.4(PDIA2):c.152C>G(p.Thr51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.279

Genes affected

PDIA2 (HGNC:14180): (protein disulfide isomerase family A member 2) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, two catalytically active thioredoxin (TRX) domains, two TRX-like domains and a C-terminal ER-retention sequence. The protein plays a role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds through its thiol isomerase, oxidase, and reductase activity. The encoded protein also possesses estradiol-binding activity and can modulate intracellular estradiol levels. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19029945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDIA2	NM_006849.4	c.152C>G	p.Thr51Ser	missense_variant	1/11	ENST00000219406.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA2	ENST00000219406.11	c.152C>G	p.Thr51Ser	missense_variant	1/11	1	NM_006849.4	P2
PDIA2	ENST00000404312.5	c.152C>G	p.Thr51Ser	missense_variant	1/11	5		A2
PDIA2	ENST00000456379.1	c.143C>G	p.Thr48Ser	missense_variant	1/5	5
PDIA2	ENST00000467212.5	n.158C>G		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458686 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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.152C>G (p.T51S) alteration is located in exon 1 (coding exon 1) of the PDIA2 gene. This alteration results from a C to G substitution at nucleotide position 152, causing the threonine (T) at amino acid position 51 to be replaced by a serine (S). 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	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Benign	0.80
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.42	N;N
REVEL	Benign	0.051
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.39	B;.
Vest4		0.30
MutPred		0.55		Gain of disorder (P = 0.0504);Gain of disorder (P = 0.0504);
MVP		0.46
ClinPred		0.36	T
GERP RS		-0.0010
Varity_R		0.042
gMVP		0.45

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: rs1389951094; hg19: chr16-333321;