16-283315-G-A

Variant summary

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

The NM_006849.4(PDIA2):c.146G>A(p.Arg49His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,609,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.923

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=0.06920612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDIA2	NM_006849.4	c.146G>A	p.Arg49His	missense_variant	1/11	ENST00000219406.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA2	ENST00000219406.11	c.146G>A	p.Arg49His	missense_variant	1/11	1	NM_006849.4	P2
PDIA2	ENST00000404312.5	c.146G>A	p.Arg49His	missense_variant	1/11	5		A2
PDIA2	ENST00000456379.1	c.137G>A	p.Arg46His	missense_variant	1/5	5
PDIA2	ENST00000467212.5	n.152G>A		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000409 AC: 10 AN: 244276 Hom.: 0 AF XY: 0.0000450 AC XY: 6 AN XY: 133364

Gnomad AFR exome AF: 0.0000672

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1457248 Hom.: 0 Cov.: 32 AF XY: 0.0000317 AC XY: 23 AN XY: 724838

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: 0.000303

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.00

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

Dec 21, 2023

The c.146G>A (p.R49H) alteration is located in exon 1 (coding exon 1) of the PDIA2 gene. This alteration results from a G to A substitution at nucleotide position 146, causing the arginine (R) at amino acid position 49 to be replaced by a histidine (H). 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	0.070
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	8.6
Dann	Benign	0.95
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.050
Sift	Benign	0.055	T;T
Sift4G	Benign	0.072	T;T
Polyphen		0.0040	B;.
Vest4		0.12
MutPred		0.46		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.33
ClinPred		0.014	T
GERP RS		-3.3
Varity_R		0.034
gMVP		0.39

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: rs757796245; hg19: chr16-333315;