Genetic Variant EMC2:p.Pro186Ser (chr8-108475928-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16

Variant links:

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]

EMC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC2	NM_014673.5 link	c.556C>T	p.Pro186Ser	missense_variant	Exon 8 of 11	ENST00000220853.8	NP_055488.1	Q15006
EMC2	NM_001329493.2 link	c.583C>T	p.Pro195Ser	missense_variant	Exon 8 of 11		NP_001316422.1
EMC2	NM_001329495.2 link	c.559C>T	p.Pro187Ser	missense_variant	Exon 9 of 12		NP_001316424.1
EMC2	NR_138033.2 link	n.533C>T		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EMC2	ENST00000220853.8 link	c.556C>T	p.Pro186Ser	missense_variant	Exon 8 of 11	1	NM_014673.5	ENSP00000220853.3	Q15006
EMC2	ENST00000519642.1 link	c.350+5807C>T		intron_variant	Intron 5 of 5	3		ENSP00000428040.1	H0YAS9
EMC2	ENST00000519450.2 link	n.2078C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2
EMC2	ENST00000520294.5 link	n.279C>T		non_coding_transcript_exon_variant	Exon 4 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151732

Hom.:

Cov.:

show subpopulations

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:

AN:

1448102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74076

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556C>T (p.P186S) alteration is located in exon 8 (coding exon 8) of the EMC2 gene. This alteration results from a C to T substitution at nucleotide position 556, causing the proline (P) at amino acid position 186 to be replaced by a serine (S). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.77

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.67

Sift

Benign

0.048

Sift4G

Uncertain

0.0060

Polyphen

0.97

Vest4

0.84

MutPred

0.86

Loss of stability (P = 0.2016);

MVP

0.90

MPC

0.93

ClinPred

0.99

GERP RS

5.7

Varity_R

0.83

gMVP

0.78

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over