8-108486560-G-C

Variant names:

• chr8-108486560-G-C
• rs1811143617
• NM_014673.5:c.856G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014673.5(EMC2):​c.856G>C​(p.Glu286Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E286K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EMC2 NM_014673.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

Genes affected

EMC2 (HGNC:28963): (ER membrane protein complex subunit 2) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Located in endoplasmic reticulum membrane. Is extrinsic component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36533242).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014673.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC2	NM_014673.5	MANE Select	c.856G>C	p.Glu286Gln	missense	Exon 11 of 11	NP_055488.1	Q15006
	EMC2	NM_001329493.2		c.883G>C	p.Glu295Gln	missense	Exon 11 of 11	NP_001316422.1
	EMC2	NM_001329495.2		c.859G>C	p.Glu287Gln	missense	Exon 12 of 12	NP_001316424.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC2	ENST00000220853.8	TSL:1 MANE Select	c.856G>C	p.Glu286Gln	missense	Exon 11 of 11	ENSP00000220853.3	Q15006
	EMC2	ENST00000890427.1		c.883G>C	p.Glu295Gln	missense	Exon 11 of 11	ENSP00000560486.1
	EMC2	ENST00000890429.1		c.880G>C	p.Glu294Gln	missense	Exon 11 of 11	ENSP00000560488.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453298 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 722666

African (AFR) AF: 0.00 AC: 0 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.00 AC: 0 AN: 84458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107746

Other (OTH) AF: 0.00 AC: 0 AN: 59930

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.043	D
Sift4G	Uncertain	0.060	T
Polyphen		0.98	D
Vest4		0.34
MutPred		0.39		Loss of ubiquitination at K283 (P = 0.026)
MVP		0.72
MPC		0.32
ClinPred		0.96	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.70
Mutation Taster		=43/57	disease causing

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: rs1811143617; hg19: chr8-109498789;