20-35115804-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018217.3(EDEM2):​c.1366G>A​(p.Ala456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,624 control chromosomes in the GnomAD database, including 22,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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: 𝑓 0.13 (1517 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20681 hom.)
• Consequence: EDEM2 NM_018217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560
• Publications: 49 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026990771).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDEM2	NM_018217.3	c.1366G>A	p.Ala456Thr	missense_variant	Exon 11 of 11	ENST00000374492.8	NP_060687.2
EDEM2	NM_001145025.2	c.1255G>A	p.Ala419Thr	missense_variant	Exon 10 of 10		NP_001138497.1
MMP24-AS1-EDEM2	NM_001355008.2	c.1243G>A	p.Ala415Thr	missense_variant	Exon 15 of 15		NP_001341937.1
EDEM2	NR_026728.2	n.1660G>A		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>A	p.Ala456Thr	missense_variant	Exon 11 of 11	1	NM_018217.3	ENSP00000363616.3
EDEM2	ENST00000374491.3	c.1255G>A	p.Ala419Thr	missense_variant	Exon 10 of 10	1		ENSP00000363615.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19118 AN: 151676 Hom.: 1514 Cov.: 32

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.0962

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.158 AC: 39580 AN: 251280 AF XY: 0.166

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0911

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.164 AC: 239956 AN: 1461832 Hom.: 20681 Cov.: 33 AF XY: 0.167 AC XY: 121425 AN XY: 727210

African (AFR) AF: 0.0251 AC: 841 AN: 33480

American (AMR) AF: 0.0938 AC: 4196 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5621 AN: 26134

East Asian (EAS) AF: 0.116 AC: 4597 AN: 39700

South Asian (SAS) AF: 0.205 AC: 17661 AN: 86258

European-Finnish (FIN) AF: 0.193 AC: 10301 AN: 53418

Middle Eastern (MID) AF: 0.237 AC: 1368 AN: 5768

European-Non Finnish (NFE) AF: 0.167 AC: 185937 AN: 1111966

Other (OTH) AF: 0.156 AC: 9434 AN: 60392

GnomAD4 genome AF: 0.126 AC: 19122 AN: 151792 Hom.: 1517 Cov.: 32 AF XY: 0.127 AC XY: 9438 AN XY: 74188

African (AFR) AF: 0.0277 AC: 1142 AN: 41192

American (AMR) AF: 0.118 AC: 1796 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 692 AN: 3472

East Asian (EAS) AF: 0.0962 AC: 497 AN: 5164

South Asian (SAS) AF: 0.208 AC: 1005 AN: 4826

European-Finnish (FIN) AF: 0.193 AC: 2038 AN: 10560

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11452 AN: 67992

Other (OTH) AF: 0.142 AC: 299 AN: 2104

Alfa AF: 0.161 Hom.: 6983

Bravo AF: 0.115

TwinsUK AF: 0.167 AC: 620

ALSPAC AF: 0.160 AC: 617

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.177 AC: 1521

ExAC AF: 0.159 AC: 19240

Asia WGS AF: 0.177 AC: 617 AN: 3478

EpiCase AF: 0.179

EpiControl AF: 0.183

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.9
DANN	Benign	0.78
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.
PhyloP100		0.56
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.0090
Sift	Benign	0.60	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0010	B;B
Vest4		0.033
MPC		0.33
ClinPred		0.00030	T
GERP RS		-0.27
Varity_R		0.017
gMVP		0.28
Mutation Taster		=89/11	polymorphism (auto)

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: rs3746429; hg19: chr20-33703607; COSMIC: COSV63259551; COSMIC: COSV63259551;