Genetic Variant PDIA2:p.Pro131Pro (chr16-284580-G-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_006849.4(PDIA2):c.393G>C(p.Pro131Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,611,126 control chromosomes in the GnomAD database, including 60,844 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 0.28 ( 5926 hom., cov: 34)

Exomes 𝑓: 0.27 ( 54918 hom. )

Consequence

PDIA2
NM_006849.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.70

Publications

16 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.085).

BP7

Synonymous conserved (PhyloP=-1.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA2	NM_006849.4 link	c.393G>C	p.Pro131Pro	synonymous_variant	Exon 2 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.393G>C	p.Pro131Pro	synonymous_variant	Exon 2 of 11	1	NM_006849.4	ENSP00000219406.7		Q13087-1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41993

AN:

152110

Hom.:

5914

Cov.:

show subpopulations

Gnomad AFR

AF:

0.309

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.250

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.277

GnomAD2 exomes

AF:

0.246

AC:

59713

AN:

243220

AF XY:

0.252

show subpopulations

Gnomad AFR exome

AF:

0.304

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.146

Gnomad FIN exome

AF:

0.256

Gnomad NFE exome

AF:

0.278

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.272

AC:

397276

AN:

1458898

Hom.:

54918

Cov.:

AF XY:

0.272

AC XY:

197274

AN XY:

725610

show subpopulations

African (AFR)

AF:

0.316

AC:

10579

AN:

33462

American (AMR)

AF:

0.150

AC:

6665

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7866

AN:

26054

East Asian (EAS)

AF:

0.126

AC:

4984

AN:

39638

South Asian (SAS)

AF:

0.246

AC:

21176

AN:

85946

European-Finnish (FIN)

AF:

0.254

AC:

13192

AN:

52038

Middle Eastern (MID)

AF:

0.341

AC:

1964

AN:

5762

European-Non Finnish (NFE)

AF:

0.283

AC:

314406

AN:

1111160

Other (OTH)

AF:

0.273

AC:

16444

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

19780

39559

59339

79118

98898

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10472

20944

31416

41888

52360

<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:

0.276

AC:

42048

AN:

152228

Hom.:

5926

Cov.:

AF XY:

0.273

AC XY:

20340

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.309

AC:

12836

AN:

41528

American (AMR)

AF:

0.215

AC:

3283

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1018

AN:

3470

East Asian (EAS)

AF:

0.143

AC:

739

AN:

5178

South Asian (SAS)

AF:

0.243

AC:

1170

AN:

4824

European-Finnish (FIN)

AF:

0.250

AC:

2652

AN:

10608

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.284

AC:

19336

AN:

68002

Other (OTH)

AF:

0.280

AC:

592

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1656

3311

4967

6622

8278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.241

Hom.:

1499

Bravo

AF:

0.275

Asia WGS

AF:

0.225

AC:

782

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0060

(source)

DANN

Benign

0.73

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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