rs419949

Variant names:

• chr16-284890-G-A
• rs419949
• NM_006849.4:c.553G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-284890-G-A
• chr16-284890-G-C

Variant summary

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

The NM_006849.4(PDIA2):​c.553G>A​(p.Glu185Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,612,818 control chromosomes in the GnomAD database, including 28,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.17 (2345 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26058 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194
• Publications: 30 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=0.0026741922).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA2	NM_006849.4	c.553G>A	p.Glu185Lys	missense_variant	Exon 4 of 11	ENST00000219406.11	NP_006840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA2	ENST00000219406.11	c.553G>A	p.Glu185Lys	missense_variant	Exon 4 of 11	1	NM_006849.4	ENSP00000219406.7

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25275 AN: 152162 Hom.: 2343 Cov.: 33

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.143 AC: 35378 AN: 247566 AF XY: 0.142

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0723

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.000780

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.180 AC: 262645 AN: 1460538 Hom.: 26058 Cov.: 74 AF XY: 0.176 AC XY: 128182 AN XY: 726562

African (AFR) AF: 0.168 AC: 5633 AN: 33472

American (AMR) AF: 0.0768 AC: 3434 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3710 AN: 26122

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39698

South Asian (SAS) AF: 0.0462 AC: 3983 AN: 86254

European-Finnish (FIN) AF: 0.195 AC: 10180 AN: 52272

Middle Eastern (MID) AF: 0.132 AC: 761 AN: 5768

European-Non Finnish (NFE) AF: 0.203 AC: 225295 AN: 1111878

Other (OTH) AF: 0.160 AC: 9629 AN: 60364

GnomAD4 genome AF: 0.166 AC: 25296 AN: 152280 Hom.: 2345 Cov.: 33 AF XY: 0.160 AC XY: 11915 AN XY: 74454

African (AFR) AF: 0.164 AC: 6827 AN: 41556

American (AMR) AF: 0.103 AC: 1578 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3466

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0387 AC: 187 AN: 4828

European-Finnish (FIN) AF: 0.179 AC: 1899 AN: 10616

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13614 AN: 68000

Other (OTH) AF: 0.147 AC: 310 AN: 2114

Alfa AF: 0.182 Hom.: 7316

Bravo AF: 0.164

TwinsUK AF: 0.211 AC: 784

ALSPAC AF: 0.204 AC: 785

ESP6500AA AF: 0.147 AC: 607

ESP6500EA AF: 0.198 AC: 1658

ExAC AF: 0.147 AC: 17752

Asia WGS AF: 0.0370 AC: 131 AN: 3478

EpiCase AF: 0.183

EpiControl AF: 0.185

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		0.19
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.037
Sift	Benign	0.15	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.024	B;.
Vest4		0.10
ClinPred		0.0016	T
GERP RS		0.30
Varity_R		0.11
gMVP		0.62
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs419949; hg19: chr16-334890; COSMIC: COSV51988720; COSMIC: COSV51988720;