16-284580-G-C

Variant names:

• chr16-284580-G-C
• rs432925
• NM_006849.4:c.393G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 16 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA2	NM_006849.4	MANE Select	c.393G>C	p.Pro131Pro	synonymous	Exon 2 of 11	NP_006840.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA2	ENST00000219406.11	TSL:1 MANE Select	c.393G>C	p.Pro131Pro	synonymous	Exon 2 of 11	ENSP00000219406.7
	PDIA2	ENST00000482665.1	TSL:1	n.429G>C		non_coding_transcript_exon	Exon 1 of 7
	PDIA2	ENST00000404312.5	TSL:5	c.393G>C	p.Pro131Pro	synonymous	Exon 2 of 11	ENSP00000384410.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41993 AN: 152110 Hom.: 5914 Cov.: 34

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

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.: 71 AF XY: 0.272 AC XY: 197274 AN XY: 725610

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

GnomAD4 genome AF: 0.276 AC: 42048 AN: 152228 Hom.: 5926 Cov.: 34 AF XY: 0.273 AC XY: 20340 AN XY: 74426

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0060
DANN	Benign	0.73
PhyloP100		-1.7
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: rs432925; hg19: chr16-334580; COSMIC: COSV51995239; COSMIC: COSV51995239;