20-35115634-C-A

Position:

• chr20-35115634-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018217.3(EDEM2):​c.1536G>T​(p.Arg512Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDEM2 NM_018217.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061107844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDEM2	NM_018217.3	c.1536G>T	p.Arg512Ser	missense_variant	11/11	ENST00000374492.8	NP_060687.2
EDEM2	NM_001145025.2	c.1425G>T	p.Arg475Ser	missense_variant	10/10		NP_001138497.1
MMP24-AS1-EDEM2	NM_001355008.2	c.1413G>T	p.Arg471Ser	missense_variant	15/15		NP_001341937.1
EDEM2	NR_026728.2	n.1830G>T		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDEM2	ENST00000374492.8	c.1536G>T	p.Arg512Ser	missense_variant	11/11	1	NM_018217.3	ENSP00000363616.3
EDEM2	ENST00000374491.3	c.1425G>T	p.Arg475Ser	missense_variant	10/10	1		ENSP00000363615.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.1536G>T (p.R512S) alteration is located in exon 11 (coding exon 11) of the EDEM2 gene. This alteration results from a G to T substitution at nucleotide position 1536, causing the arginine (R) at amino acid position 512 to be replaced by a serine (S). 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	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.3
DANN	Benign	0.76
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.010
Sift	Benign	0.093	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0030	B;B
Vest4		0.27
MutPred		0.31		Gain of phosphorylation at R512 (P = 0.0219);.;
MVP		0.19
MPC		0.38
ClinPred		0.020	T
GERP RS		-1.5
Varity_R		0.087
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-33703437;