chr20-35115804-C-T

Position:

• chr20-35115804-C-T

Variant summary

Our verdict is Benign. Variant got -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. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
EDEM2	NM_018217.3	c.1366G>A	p.Ala456Thr	missense_variant	11/11	ENST00000374492.8	NP_060687.2
MMP24-AS1-EDEM2	NM_001355008.2	c.1243G>A	p.Ala415Thr	missense_variant	15/15		NP_001341937.1
EDEM2	NM_001145025.2	c.1255G>A	p.Ala419Thr	missense_variant	10/10		NP_001138497.1
EDEM2	NR_026728.2	n.1660G>A		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDEM2	ENST00000374492.8	c.1366G>A	p.Ala456Thr	missense_variant	11/11	1	NM_018217.3	ENSP00000363616	P1
EDEM2	ENST00000374491.3	c.1255G>A	p.Ala419Thr	missense_variant	10/10	1		ENSP00000363615

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

GnomAD3 exomes AF: 0.158 AC: 39580 AN: 251280 Hom.: 3512 AF XY: 0.166 AC XY: 22522 AN XY: 135806

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 SAS exome AF: 0.211

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

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.0938

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.156

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

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.0962

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.142

Alfa AF: 0.166 Hom.: 5457

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;.
MutationTaster	Benign	1.0	P;P;P;P
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

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

Publications

LitVar

Other links and lift over

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