chr8-108475928-C-T

Variant names:

• chr8-108475928-C-T
• rs1810938036
• NM_014673.5:c.556C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014673.5(EMC2):​c.556C>T​(p.Pro186Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,599,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EMC2 NM_014673.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

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.556C>T	p.Pro186Ser	missense	Exon 8 of 11	NP_055488.1	Q15006
	EMC2	NM_001329493.2		c.583C>T	p.Pro195Ser	missense	Exon 8 of 11	NP_001316422.1
	EMC2	NM_001329495.2		c.559C>T	p.Pro187Ser	missense	Exon 9 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.556C>T	p.Pro186Ser	missense	Exon 8 of 11	ENSP00000220853.3	Q15006
	EMC2	ENST00000890427.1		c.583C>T	p.Pro195Ser	missense	Exon 8 of 11	ENSP00000560486.1
	EMC2	ENST00000890429.1		c.580C>T	p.Pro194Ser	missense	Exon 8 of 11	ENSP00000560488.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 32

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448102 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 720644

African (AFR) AF: 0.00 AC: 0 AN: 32754

American (AMR) AF: 0.00 AC: 0 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39014

South Asian (SAS) AF: 0.00 AC: 0 AN: 84516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104422

Other (OTH) AF: 0.00 AC: 0 AN: 59766

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74076

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67794

Other (OTH) AF: 0.00 AC: 0 AN: 2076

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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.67
Sift	Benign	0.048	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.84
MutPred		0.86		Loss of stability (P = 0.2016)
MVP		0.90
MPC		0.93
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.78
Mutation Taster		=56/44	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: rs1810938036; hg19: chr8-109488157;