chr2-232567124-C-T

Position:

• chr2-232567124-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004846.4(EIF4E2):​c.575C>T​(p.Thr192Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4E2 NM_004846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4E2	NM_004846.4	c.575C>T	p.Thr192Ile	missense_variant	6/7	ENST00000258416.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4E2	ENST00000258416.8	c.575C>T	p.Thr192Ile	missense_variant	6/7	1	NM_004846.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.575C>T (p.T192I) alteration is located in exon 6 (coding exon 6) of the EIF4E2 gene. This alteration results from a C to T substitution at nucleotide position 575, causing the threonine (T) at amino acid position 192 to be replaced by an isoleucine (I). 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	0.78
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.;T;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D
REVEL	Benign	0.29
Sift	Benign	0.17	T;T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T
Polyphen		0.29	B;.;.;.;P;.;.;.
Vest4		0.60
MutPred		0.66		Loss of disorder (P = 0.0297);Loss of disorder (P = 0.0297);Loss of disorder (P = 0.0297);Loss of disorder (P = 0.0297);.;.;.;.;
MVP		0.33
MPC		1.1
ClinPred		0.94	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233431834;