NM_006849.4:c.1504C>T

Variant names:

• chr16-286916-C-T
• rs1048786
• NM_006849.4:c.1504C>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.1504C>T​(p.Pro502Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,597,558 control chromosomes in the GnomAD database, including 20,332 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 0.13 (1481 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18851 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.462
• Publications: 23 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=0.0020225644).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA2	NM_006849.4	c.1504C>T	p.Pro502Ser	missense_variant	Exon 10 of 11	ENST00000219406.11	NP_006840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA2	ENST00000219406.11	c.1504C>T	p.Pro502Ser	missense_variant	Exon 10 of 11	1	NM_006849.4	ENSP00000219406.7

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19924 AN: 152146 Hom.: 1480 Cov.: 33

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.144 AC: 32046 AN: 222102 AF XY: 0.151

Gnomad AFR exome AF: 0.0694

Gnomad AMR exome AF: 0.0826

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.160 AC: 230676 AN: 1445294 Hom.: 18851 Cov.: 53 AF XY: 0.160 AC XY: 115295 AN XY: 718594

African (AFR) AF: 0.0661 AC: 2150 AN: 32510

American (AMR) AF: 0.0835 AC: 3369 AN: 40324

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3833 AN: 25616

East Asian (EAS) AF: 0.108 AC: 4247 AN: 39362

South Asian (SAS) AF: 0.198 AC: 16759 AN: 84792

European-Finnish (FIN) AF: 0.134 AC: 6893 AN: 51584

Middle Eastern (MID) AF: 0.152 AC: 861 AN: 5676

European-Non Finnish (NFE) AF: 0.166 AC: 183256 AN: 1105854

Other (OTH) AF: 0.156 AC: 9308 AN: 59576

GnomAD4 genome AF: 0.131 AC: 19929 AN: 152264 Hom.: 1481 Cov.: 33 AF XY: 0.131 AC XY: 9757 AN XY: 74444

African (AFR) AF: 0.0694 AC: 2884 AN: 41580

American (AMR) AF: 0.113 AC: 1734 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3468

East Asian (EAS) AF: 0.126 AC: 654 AN: 5170

South Asian (SAS) AF: 0.200 AC: 964 AN: 4816

European-Finnish (FIN) AF: 0.139 AC: 1471 AN: 10616

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11254 AN: 67996

Other (OTH) AF: 0.143 AC: 302 AN: 2114

Alfa AF: 0.144 Hom.: 1378

Bravo AF: 0.124

TwinsUK AF: 0.165 AC: 613

ALSPAC AF: 0.171 AC: 658

ESP6500AA AF: 0.0692 AC: 252

ESP6500EA AF: 0.158 AC: 1286

ExAC AF: 0.137 AC: 16344

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.8
DANN	Benign	0.86
DEOGEN2	Benign	0.0084	T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;.;.
PhyloP100		0.46
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.015
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.56	T;T;T
Vest4		0.10
ClinPred		0.00082	T
GERP RS		2.3
Varity_R		0.057
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1048786; hg19: chr16-336916; COSMIC: COSV51984040; COSMIC: COSV51984040;