16-284397-G-A

Variant names:

• chr16-284397-G-A
• rs1329266665
• NM_006849.4:c.210G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006849.4(PDIA2):​c.210G>A​(p.Trp70*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000071 in 1,409,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PDIA2 NM_006849.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.58
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA2	NM_006849.4	MANE Select	c.210G>A	p.Trp70*	stop_gained	Exon 2 of 11	NP_006840.2	Q13087-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDIA2	ENST00000219406.11	TSL:1 MANE Select	c.210G>A	p.Trp70*	stop_gained	Exon 2 of 11	ENSP00000219406.7	Q13087-1
	PDIA2	ENST00000482665.1	TSL:1	n.246G>A		non_coding_transcript_exon	Exon 1 of 7
	PDIA2	ENST00000404312.5	TSL:5	c.210G>A	p.Trp70*	stop_gained	Exon 2 of 11	ENSP00000384410.1	Q13087-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000172 AC: 3 AN: 173990 AF XY: 0.0000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000766

Gnomad FIN exome AF: 0.0000959

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409150 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 697634

African (AFR) AF: 0.00 AC: 0 AN: 32516

American (AMR) AF: 0.0000263 AC: 1 AN: 37996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25362

East Asian (EAS) AF: 0.00 AC: 0 AN: 37372

South Asian (SAS) AF: 0.00 AC: 0 AN: 80868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091076

Other (OTH) AF: 0.00 AC: 0 AN: 58624

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	50
DANN	Uncertain	0.99
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.6
Vest4		0.34
ClinPred		0.99	D
GERP RS		4.1
Mutation Taster		=29/171	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1329266665; hg19: chr16-334397;