rs1819140626

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-108455895-T-A
• chr8-108455895-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014673.5(EMC2):​c.328T>A​(p.Tyr110Asn) 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. 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. Y110H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: EMC2 NM_014673.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

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.328T>A	p.Tyr110Asn	missense	Exon 5 of 11	NP_055488.1	Q15006
	EMC2	NM_001329493.2		c.355T>A	p.Tyr119Asn	missense	Exon 5 of 11	NP_001316422.1
	EMC2	NM_001329495.2		c.331T>A	p.Tyr111Asn	missense	Exon 6 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.328T>A	p.Tyr110Asn	missense	Exon 5 of 11	ENSP00000220853.3	Q15006
	EMC2	ENST00000890427.1		c.355T>A	p.Tyr119Asn	missense	Exon 5 of 11	ENSP00000560486.1
	EMC2	ENST00000890429.1		c.352T>A	p.Tyr118Asn	missense	Exon 5 of 11	ENSP00000560488.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.36e-7 AC: 1 AN: 1195682 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 603652

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24654

American (AMR) AF: 0.00 AC: 0 AN: 28624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21996

East Asian (EAS) AF: 0.00 AC: 0 AN: 33206

South Asian (SAS) AF: 0.00 AC: 0 AN: 66040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5028

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 915106

Other (OTH) AF: 0.00 AC: 0 AN: 50120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.64		Gain of disorder (P = 0.0147)
MVP		0.87
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.93
Mutation Taster		=47/53	disease causing

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: rs1819140626; hg19: chr8-109468124;