rs400037

Variant names:

• chr16-286396-G-A
• rs400037
• NM_006849.4:c.1163G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006849.4(PDIA2):​c.1163G>A​(p.Arg388Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,610,242 control chromosomes in the GnomAD database, including 33,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (3959 hom., cov: 24)
  • Exomes 𝑓: 0.19 (29149 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 45 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=0.006074339).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA2	NM_006849.4	c.1163G>A	p.Arg388Gln	missense_variant	Exon 8 of 11	ENST00000219406.11	NP_006840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA2	ENST00000219406.11	c.1163G>A	p.Arg388Gln	missense_variant	Exon 8 of 11	1	NM_006849.4	ENSP00000219406.7

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32180 AN: 149350 Hom.: 3941 Cov.: 24

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0474

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.166 AC: 41299 AN: 248180 AF XY: 0.161

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0445

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.192 AC: 281072 AN: 1460774 Hom.: 29149 Cov.: 46 AF XY: 0.189 AC XY: 137011 AN XY: 726678

African (AFR) AF: 0.331 AC: 11069 AN: 33478

American (AMR) AF: 0.111 AC: 4953 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3836 AN: 26126

East Asian (EAS) AF: 0.0713 AC: 2829 AN: 39700

South Asian (SAS) AF: 0.0654 AC: 5637 AN: 86258

European-Finnish (FIN) AF: 0.196 AC: 10325 AN: 52554

Middle Eastern (MID) AF: 0.145 AC: 837 AN: 5766

European-Non Finnish (NFE) AF: 0.208 AC: 230784 AN: 1111818

Other (OTH) AF: 0.179 AC: 10802 AN: 60368

GnomAD4 genome AF: 0.216 AC: 32243 AN: 149468 Hom.: 3959 Cov.: 24 AF XY: 0.209 AC XY: 15238 AN XY: 72920

African (AFR) AF: 0.316 AC: 12726 AN: 40294

American (AMR) AF: 0.142 AC: 2135 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 492 AN: 3448

East Asian (EAS) AF: 0.0477 AC: 239 AN: 5014

South Asian (SAS) AF: 0.0544 AC: 255 AN: 4688

European-Finnish (FIN) AF: 0.178 AC: 1834 AN: 10330

Middle Eastern (MID) AF: 0.186 AC: 54 AN: 290

European-Non Finnish (NFE) AF: 0.204 AC: 13771 AN: 67416

Other (OTH) AF: 0.181 AC: 372 AN: 2060

Alfa AF: 0.203 Hom.: 9335

Bravo AF: 0.222

TwinsUK AF: 0.213 AC: 788

ALSPAC AF: 0.208 AC: 803

ESP6500AA AF: 0.299 AC: 1142

ESP6500EA AF: 0.204 AC: 1679

ExAC AF: 0.172 AC: 20746

Asia WGS AF: 0.0820 AC: 287 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.65
DEOGEN2	Benign	0.0067	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.15	N;.;.
PhyloP100		-0.17
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.98	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.058
ClinPred		0.0012	T
GERP RS		-2.3
Varity_R		0.026
gMVP		0.52
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs400037; hg19: chr16-336396; COSMIC: COSV51992150; COSMIC: COSV51992150;