12-112022416-G-C

Variant names:

• chr12-112022416-G-C
• NM_006817.4:c.550G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006817.4(ERP29):​c.550G>C​(p.Gly184Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERP29 NM_006817.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71
• Publications: 0 publications found

Genes affected

ERP29 (HGNC:13799): (endoplasmic reticulum protein 29) This gene encodes a protein which localizes to the lumen of the endoplasmic reticulum (ER). It is a member of the protein disulfide isomerase (PDI) protein family but lacks an active thioredoxin motif, suggesting that this protein does not function as a disulfide isomerase. The canonical protein dimerizes and is thought to play a role in the processing of secretory proteins within the ER. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41259667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERP29	NM_006817.4	c.550G>C	p.Gly184Arg	missense_variant	Exon 3 of 3	ENST00000261735.4	NP_006808.1
ERP29	NM_001034025.2	c.*249G>C		3_prime_UTR_variant	Exon 2 of 2		NP_001029197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERP29	ENST00000261735.4	c.550G>C	p.Gly184Arg	missense_variant	Exon 3 of 3	1	NM_006817.4	ENSP00000261735.3
ERP29	ENST00000546477.1	c.247G>C	p.Gly83Arg	missense_variant	Exon 3 of 3	3		ENSP00000449018.1
ERP29	ENST00000455836.1	c.*249G>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000412083.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.550G>C (p.G184R) alteration is located in exon 3 (coding exon 3) of the ERP29 gene. This alteration results from a G to C substitution at nucleotide position 550, causing the glycine (G) at amino acid position 184 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		6.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.0090	B;.
Vest4		0.51
MutPred		0.56		Gain of solvent accessibility (P = 0.0328);.;
MVP		0.31
MPC		0.24
ClinPred		0.88	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.88
Mutation Taster		=50/50

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

hg19: chr12-112460220;