8-108455895-T-C

Variant names:

• chr8-108455895-T-C
• rs1819140626
• NM_014673.5:c.328T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014673.5(EMC2):​c.328T>C​(p.Tyr110His) variant causes a missense change. The variant allele was found at a frequency of 0.000000836 in 1,195,682 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: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: EMC2 NM_014673.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.86

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC2	NM_014673.5	c.328T>C	p.Tyr110His	missense_variant	Exon 5 of 11	ENST00000220853.8	NP_055488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC2	ENST00000220853.8	c.328T>C	p.Tyr110His	missense_variant	Exon 5 of 11	1	NM_014673.5	ENSP00000220853.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.36e-7 AC: 1 AN: 1195682 Hom.: 0 Cov.: 16 AF XY: 0.00000166 AC XY: 1 AN XY: 603652

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: 0.0000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328T>C (p.Y110H) alteration is located in exon 5 (coding exon 5) of the EMC2 gene. This alteration results from a T to C substitution at nucleotide position 328, causing the tyrosine (Y) at amino acid position 110 to be replaced by a histidine (H). 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	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.2	.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.66		.;Loss of phosphorylation at Y110 (P = 0.0171);
MVP		0.87
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.87

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

Other links and lift over

dbSNP: rs1819140626; hg19: chr8-109468124;