8-108486560-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3298167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC2	NM_014673.5	c.856G>A	p.Glu286Lys	missense_variant	Exon 11 of 11	ENST00000220853.8	NP_055488.1
EMC2	NM_001329493.2	c.883G>A	p.Glu295Lys	missense_variant	Exon 11 of 11		NP_001316422.1
EMC2	NM_001329495.2	c.859G>A	p.Glu287Lys	missense_variant	Exon 12 of 12		NP_001316424.1
EMC2	NR_138033.2	n.833G>A		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC2	ENST00000220853.8	c.856G>A	p.Glu286Lys	missense_variant	Exon 11 of 11	1	NM_014673.5	ENSP00000220853.3
EMC2	ENST00000519642.1	c.399G>A	p.Ser133Ser	synonymous_variant	Exon 6 of 6	3		ENSP00000428040.1
EMC2	ENST00000519450.2	n.2378G>A		non_coding_transcript_exon_variant	Exon 4 of 4	2
EMC2	ENST00000520294.5	n.579G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5

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

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.856G>A (p.E286K) alteration is located in exon 11 (coding exon 11) of the EMC2 gene. This alteration results from a G to A substitution at nucleotide position 856, causing the glutamic acid (E) at amino acid position 286 to be replaced by a lysine (K). 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	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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1811143617; hg19: chr8-109498789;