chr16-285373-C-T

Variant names:

• chr16-285373-C-T
• rs2685127
• NM_006849.4:c.857C>T

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PDIA2	NM_006849.4	c.857C>T	p.Thr286Met	missense_variant	Exon 6 of 11	ENST00000219406.11	NP_006840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA2	ENST00000219406.11	c.857C>T	p.Thr286Met	missense_variant	Exon 6 of 11	1	NM_006849.4	ENSP00000219406.7

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

GnomAD2 exomes AF: 0.0901 AC: 22313 AN: 247586 AF XY: 0.0876

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 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

African (AFR) AF: 0.163 AC: 5455 AN: 33474

American (AMR) AF: 0.0464 AC: 2073 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 1626 AN: 26118

East Asian (EAS) AF: 0.0109 AC: 433 AN: 39696

South Asian (SAS) AF: 0.0220 AC: 1895 AN: 86250

European-Finnish (FIN) AF: 0.118 AC: 6155 AN: 52352

Middle Eastern (MID) AF: 0.0501 AC: 289 AN: 5768

European-Non Finnish (NFE) AF: 0.126 AC: 140555 AN: 1111850

Other (OTH) AF: 0.0963 AC: 5815 AN: 60356

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

African (AFR) AF: 0.159 AC: 6557 AN: 41368

American (AMR) AF: 0.0647 AC: 988 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3468

East Asian (EAS) AF: 0.0138 AC: 71 AN: 5142

South Asian (SAS) AF: 0.0192 AC: 92 AN: 4794

European-Finnish (FIN) AF: 0.111 AC: 1166 AN: 10540

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8379 AN: 67886

Other (OTH) AF: 0.0974 AC: 205 AN: 2104

Alfa AF: 0.118 Hom.: 4565

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;.
PhyloP100		2.9
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
PromoterAI		0.00090	Neutral
Varity_R		0.35
gMVP		0.75
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2685127; hg19: chr16-335373; COSMIC: COSV51983461; COSMIC: COSV51983461;