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

Variant summary

Our verdict is Benign. Variant got -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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

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 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

GnomAD3 exomes

AF:

0.0901

AC:

22313

AN:

247586

Hom.:

1365

AF XY:

0.0876

AC XY:

11809

AN XY:

134874

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 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.:

AF XY:

0.110

AC XY:

79596

AN XY:

726582

show subpopulations

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.:

AF XY:

0.114

AC XY:

8429

AN XY:

74178

show subpopulations

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:

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

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;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over