Genetic Variant EIF4E2:p.Gly70Cys (chr2-232557956-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004846.4(EIF4E2):c.208G>T(p.Gly70Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,068 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. G70S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

EIF4E2
NM_004846.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Publications

1 publications found

Variant links:

Genes affected

EIF4E2 (HGNC:3293): (eukaryotic translation initiation factor 4E family member 2) Enables ubiquitin protein ligase binding activity. Involved in positive regulation of miRNA mediated inhibition of translation. Acts upstream of or within negative regulation of translation. Located in P-body. Part of mRNA cap binding activity complex. [provided by Alliance of Genome Resources, Apr 2022]

EIF4E2 links:

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ACMG classification

Classification was made for transcript

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_004846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E2	NM_004846.4	MANE Select	c.208G>T	p.Gly70Cys	missense	Exon 3 of 7	NP_004837.1	O60573-1
EIF4E2	NM_001330202.2		c.193G>T	p.Gly65Cys	missense	Exon 3 of 7	NP_001317131.1
EIF4E2	NM_001282958.2		c.208G>T	p.Gly70Cys	missense	Exon 3 of 8	NP_001269887.1	B8ZZ50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E2	ENST00000258416.8	TSL:1 MANE Select	c.208G>T	p.Gly70Cys	missense	Exon 3 of 7	ENSP00000258416.3	O60573-1
EIF4E2	ENST00000409098.5	TSL:1	c.208G>T	p.Gly70Cys	missense	Exon 3 of 7	ENSP00000386996.1	O60573-2
EIF4E2	ENST00000931066.1		c.199G>T	p.Gly67Cys	missense	Exon 3 of 7	ENSP00000601125.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

3.2

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.66

MutPred

0.51

Gain of catalytic residue at P69 (P = 0.0188)

MVP

0.60

MPC

1.9

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.59

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over