NM_014673.5:c.856G>A

Variant names:

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

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>A​(p.Glu286Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,453,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: EMC2 NM_014673.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.3298167).

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>A	p.Glu286Lys	missense	Exon 11 of 11	NP_055488.1	Q15006
	EMC2	NM_001329493.2		c.883G>A	p.Glu295Lys	missense	Exon 11 of 11	NP_001316422.1
	EMC2	NM_001329495.2		c.859G>A	p.Glu287Lys	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>A	p.Glu286Lys	missense	Exon 11 of 11	ENSP00000220853.3	Q15006
	EMC2	ENST00000890427.1		c.883G>A	p.Glu295Lys	missense	Exon 11 of 11	ENSP00000560486.1
	EMC2	ENST00000890429.1		c.880G>A	p.Glu294Lys	missense	Exon 11 of 11	ENSP00000560488.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1453298 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 722666

African (AFR) AF: 0.0000303 AC: 1 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: 0.0000118 AC: 1 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: 0.0000153 AC: 17 AN: 1107746

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

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.43
Sift	Benign	0.035	D
Sift4G	Benign	0.080	T
Polyphen		0.89	P
Vest4		0.34
MutPred		0.46		Gain of MoRF binding (P = 0.0024)
MVP		0.73
MPC		0.31
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.59
gMVP		0.79
Mutation Taster		=48/52	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;