rs769552669

Variant names:

• chr2-232557911-C-G
• rs769552669
• NM_004846.4:c.163C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-232557911-C-G
• chr2-232557911-C-T

Variant summary

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

The NM_004846.4(EIF4E2):​c.163C>G​(p.Pro55Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,604 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. P55S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EIF4E2 NM_004846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

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]

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, 0.767

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E2	NM_004846.4	MANE Select	c.163C>G	p.Pro55Ala	missense	Exon 3 of 7	NP_004837.1	O60573-1
	EIF4E2	NM_001330202.2		c.148C>G	p.Pro50Ala	missense	Exon 3 of 7	NP_001317131.1
	EIF4E2	NM_001282958.2		c.163C>G	p.Pro55Ala	missense	Exon 3 of 8	NP_001269887.1	B8ZZ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E2	ENST00000258416.8	TSL:1 MANE Select	c.163C>G	p.Pro55Ala	missense	Exon 3 of 7	ENSP00000258416.3	O60573-1
	EIF4E2	ENST00000409098.5	TSL:1	c.163C>G	p.Pro55Ala	missense	Exon 3 of 7	ENSP00000386996.1	O60573-2
	EIF4E2	ENST00000931066.1		c.154C>G	p.Pro52Ala	missense	Exon 3 of 7	ENSP00000601125.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461604 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111924

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.34
Sift	Benign	0.076	T
Sift4G	Uncertain	0.045	D
Polyphen		0.24	B
Vest4		0.89
MutPred		0.72		Loss of disorder (P = 0.0599)
MVP		0.47
MPC		0.92
ClinPred		0.90	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.49
Mutation Taster		=7/93	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: rs769552669; hg19: chr2-233422621;