8-108476812-C-A

Variant names:

• chr8-108476812-C-A
• rs189315527
• NM_014673.5:c.622C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014673.5(EMC2):​c.622C>A​(p.Leu208Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L208V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EMC2 NM_014673.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22207046).

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.622C>A	p.Leu208Ile	missense	Exon 9 of 11	NP_055488.1	Q15006
	EMC2	NM_001329493.2		c.649C>A	p.Leu217Ile	missense	Exon 9 of 11	NP_001316422.1
	EMC2	NM_001329495.2		c.625C>A	p.Leu209Ile	missense	Exon 10 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.622C>A	p.Leu208Ile	missense	Exon 9 of 11	ENSP00000220853.3	Q15006
	EMC2	ENST00000890427.1		c.649C>A	p.Leu217Ile	missense	Exon 9 of 11	ENSP00000560486.1
	EMC2	ENST00000890429.1		c.646C>A	p.Leu216Ile	missense	Exon 9 of 11	ENSP00000560488.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151828 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450190 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 722136

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102236

Other (OTH) AF: 0.00 AC: 0 AN: 59970

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151828 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74138

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.39
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.39
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
Polyphen		0.14	B
Vest4		0.53
MutPred		0.39		Loss of ubiquitination at K213 (P = 0.0806)
MVP		0.65
MPC		0.29
ClinPred		0.56	D
GERP RS		6.1
Varity_R		0.30
gMVP		0.33
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs189315527; hg19: chr8-109489041;