chr20-35115651-A-C

Position:

• chr20-35115651-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018217.3(EDEM2):​c.1519T>G​(p.Ser507Ala) 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. 14/21 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: 7.09

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1563187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDEM2	NM_018217.3	c.1519T>G	p.Ser507Ala	missense_variant	11/11	ENST00000374492.8	NP_060687.2
EDEM2	NM_001145025.2	c.1408T>G	p.Ser470Ala	missense_variant	10/10		NP_001138497.1
MMP24-AS1-EDEM2	NM_001355008.2	c.1396T>G	p.Ser466Ala	missense_variant	15/15		NP_001341937.1
EDEM2	NR_026728.2	n.1813T>G		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDEM2	ENST00000374492.8	c.1519T>G	p.Ser507Ala	missense_variant	11/11	1	NM_018217.3	ENSP00000363616.3
EDEM2	ENST00000374491.3	c.1408T>G	p.Ser470Ala	missense_variant	10/10	1		ENSP00000363615.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 19, 2023

The c.1519T>G (p.S507A) alteration is located in exon 11 (coding exon 11) of the EDEM2 gene. This alteration results from a T to G substitution at nucleotide position 1519, causing the serine (S) at amino acid position 507 to be replaced by an alanine (A). 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	0.077
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	0.060
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.046
Sift	Benign	0.065	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.040	B;B
Vest4		0.18
MutPred		0.29		Loss of phosphorylation at S507 (P = 0.0192);.;
MVP		0.65
MPC		0.28
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.051
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs778117289; hg19: chr20-33703454;