16-285373-C-T

Position:

• chr16-285373-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006849.4(PDIA2):​c.857C>T​(p.Thr286Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,612,320 control chromosomes in the GnomAD database, including 11,688 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1197 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10491 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019084513).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDIA2	NM_006849.4	c.857C>T	p.Thr286Met	missense_variant	6/11	ENST00000219406.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDIA2	ENST00000219406.11	c.857C>T	p.Thr286Met	missense_variant	6/11	1	NM_006849.4	P2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17855 AN: 151656 Hom.: 1196 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0985

GnomAD3 exomes AF: 0.0901 AC: 22313 AN: 247586 Hom.: 1365 AF XY: 0.0876 AC XY: 11809 AN XY: 134874

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0429

Gnomad ASJ exome AF: 0.0629

Gnomad EAS exome AF: 0.0114

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.0896

GnomAD4 exome AF: 0.112 AC: 164296 AN: 1460546 Hom.: 10491 Cov.: 65 AF XY: 0.110 AC XY: 79596 AN XY: 726582

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.0464

Gnomad4 ASJ exome AF: 0.0623

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.0963

GnomAD4 genome AF: 0.118 AC: 17871 AN: 151774 Hom.: 1197 Cov.: 32 AF XY: 0.114 AC XY: 8429 AN XY: 74178

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0647

Gnomad4 ASJ AF: 0.0672

Gnomad4 EAS AF: 0.0138

Gnomad4 SAS AF: 0.0192

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.114 Hom.: 2136

Bravo AF: 0.117

TwinsUK AF: 0.130 AC: 483

ALSPAC AF: 0.130 AC: 502

ESP6500AA AF: 0.144 AC: 587

ESP6500EA AF: 0.119 AC: 995

ExAC AF: 0.0948 AC: 11446

Asia WGS AF: 0.0280 AC: 98 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.109

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.0061	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.074
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.94	P;.
Vest4		0.23
ClinPred		0.023	T
GERP RS		3.9
Varity_R		0.35
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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; COSMIC: COSV51983461; COSMIC: COSV51983461;