16-283315-G-C

Variant names:

• chr16-283315-G-C
• rs757796245
• NM_006849.4:c.146G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006849.4(PDIA2):​c.146G>C​(p.Arg49Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PDIA2 NM_006849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.923

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11449906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDIA2	NM_006849.4	c.146G>C	p.Arg49Pro	missense_variant	Exon 1 of 11	ENST00000219406.11	NP_006840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDIA2	ENST00000219406.11	c.146G>C	p.Arg49Pro	missense_variant	Exon 1 of 11	1	NM_006849.4	ENSP00000219406.7
PDIA2	ENST00000404312.5	c.146G>C	p.Arg49Pro	missense_variant	Exon 1 of 11	5		ENSP00000384410.1
PDIA2	ENST00000456379.1	c.134G>C	p.Arg45Pro	missense_variant	Exon 1 of 5	5		ENSP00000392277.1
PDIA2	ENST00000467212.5	n.152G>C		non_coding_transcript_exon_variant	Exon 1 of 10	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.8
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.098
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.30	B;.
Vest4		0.29
MutPred		0.53		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.32
ClinPred		0.17	T
GERP RS		-3.3
Varity_R		0.27
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs757796245; hg19: chr16-333315;