Genetic Variant NM_006849.4:c.857C>T (chr16-285373-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Publications

29 publications found

Variant links:

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]

PDIA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.857C>T	p.Thr286Met	missense_variant	Exon 6 of 11	ENST00000219406.11	NP_006840.2	Q13087-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA2	ENST00000219406.11 link	c.857C>T	p.Thr286Met	missense_variant	Exon 6 of 11	1	NM_006849.4	ENSP00000219406.7		Q13087-1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17855

AN:

151656

Hom.:

1196

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.110

AC XY:

79596

AN XY:

726582

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

9502

19003

28505

38006

47508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4990

9980

14970

19960

24950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.118

AC:

17871

AN:

151774

Hom.:

1197

Cov.:

AF XY:

0.114

AC XY:

8429

AN XY:

74178

show subpopulations

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:

AN:

5142

South Asian (SAS)

AF:

0.0192

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.111

AC:

1166

AN:

10540

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.123

AC:

8379

AN:

67886

Other (OTH)

AF:

0.0974

AC:

205

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

725

1450

2175

2900

3625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:

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

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

2.9

PrimateAI

Uncertain

0.58

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

GERP RS

3.9

PromoterAI

0.00090

Neutral

(source)

Varity_R

0.35

gMVP

0.75

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over