rs768743092

Variant names:

• chr16-284453-C-T
• rs768743092
• NM_006849.4:c.266C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-284453-C-T
• chr16-284453-C-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_006849.4(PDIA2):​c.266C>T​(p.Ala89Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000882 in 1,598,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A89T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (1 hom.)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2995801).

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.266C>T	p.Ala89Val	missense	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.266C>T	p.Ala89Val	missense	Exon 2 of 11	ENSP00000219406.7	Q13087-1
	PDIA2	ENST00000482665.1	TSL:1	n.302C>T		non_coding_transcript_exon	Exon 1 of 7
	PDIA2	ENST00000404312.5	TSL:5	c.266C>T	p.Ala89Val	missense	Exon 2 of 11	ENSP00000384410.1	Q13087-2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000905 AC: 20 AN: 220912 AF XY: 0.0000916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000613

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000702

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000899 AC: 130 AN: 1446558 Hom.: 1 Cov.: 30 AF XY: 0.0000891 AC XY: 64 AN XY: 718294

African (AFR) AF: 0.0000300 AC: 1 AN: 33356

American (AMR) AF: 0.000308 AC: 13 AN: 42230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25816

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39160

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50408

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5674

European-Non Finnish (NFE) AF: 0.0000976 AC: 108 AN: 1106210

Other (OTH) AF: 0.0000334 AC: 2 AN: 59868

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74386

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000333 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.066
Sift	Benign	0.051	T
Sift4G	Benign	0.086	T
Polyphen		0.0070	B
Vest4		0.38
MutPred		0.61		Gain of catalytic residue at A89 (P = 0.0456)
MVP		0.55
ClinPred		0.065	T
GERP RS		3.0
Varity_R		0.12
gMVP		0.60
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768743092; hg19: chr16-334453;