20-35115804-C-G

Variant names:

• chr20-35115804-C-G
• rs3746429
• NM_018217.3:c.1366G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018217.3(EDEM2):​c.1366G>C​(p.Ala456Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EDEM2 NM_018217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560
• Publications: 0 publications found

Genes affected

EDEM2 (HGNC:15877): (ER degradation enhancing alpha-mannosidase like protein 2) In the endoplasmic reticulum (ER), misfolded proteins are retrotranslocated to the cytosol and degraded by the proteasome in a process known as ER-associated degradation (ERAD). EDEM2 belongs to a family of proteins involved in ERAD of glycoproteins (Mast et al., 2005 [PubMed 15537790]).[supplied by OMIM, Mar 2008]

MMP24-AS1-EDEM2 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06277394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDEM2	NM_018217.3	c.1366G>C	p.Ala456Pro	missense_variant	Exon 11 of 11	ENST00000374492.8	NP_060687.2
EDEM2	NM_001145025.2	c.1255G>C	p.Ala419Pro	missense_variant	Exon 10 of 10		NP_001138497.1
MMP24-AS1-EDEM2	NM_001355008.2	c.1243G>C	p.Ala415Pro	missense_variant	Exon 15 of 15		NP_001341937.1
EDEM2	NR_026728.2	n.1660G>C		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDEM2	ENST00000374492.8	c.1366G>C	p.Ala456Pro	missense_variant	Exon 11 of 11	1	NM_018217.3	ENSP00000363616.3
EDEM2	ENST00000374491.3	c.1255G>C	p.Ala419Pro	missense_variant	Exon 10 of 10	1		ENSP00000363615.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.58
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.23	N;.
PhyloP100		0.56
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.24
Sift	Benign	0.30	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0010	B;B
Vest4		0.29
MutPred		0.39		Gain of loop (P = 0.0312);.;
MVP		0.13
MPC		0.44
ClinPred		0.064	T
GERP RS		-0.27
Varity_R		0.058
gMVP		0.70
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3746429; hg19: chr20-33703607;