rs2685127

chr16-285373-C-Gchr16-285373-C-T

Variant summary

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

The NM_006849.4(PDIA2):c.857C>G(p.Thr286Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,580 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T286M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDIA2	NM_006849.4	c.857C>G	p.Thr286Arg	missense_variant	6/11	ENST00000219406.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA2	ENST00000219406.11	c.857C>G	p.Thr286Arg	missense_variant	6/11	1	NM_006849.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460580 Hom.: 0 Cov.: 65 AF XY: 0.00 AC XY: 0 AN XY: 726598

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.0025	P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.072
Sift	Benign	0.051	T;T
Sift4G	Benign	0.088	T;T
Polyphen		0.51	P;.
Vest4		0.27
MutPred		0.46		Gain of MoRF binding (P = 0.0854);.;
MVP		0.60
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.57
gMVP		0.87

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: rs2685127; hg19: chr16-335373;