10-70420074-C-A

Variant names:

• chr10-70420074-C-A
• rs753546022
• NM_004096.5:c.306C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004096.5(EIF4EBP2):​c.306C>A​(p.Asn102Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EIF4EBP2 NM_004096.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

EIF4EBP2 (HGNC:3289): (eukaryotic translation initiation factor 4E binding protein 2) This gene encodes a member of the eukaryotic translation initiation factor 4E binding protein family. The gene products of this family bind eIF4E and inhibit translation initiation. However, insulin and other growth factors can release this inhibition via a phosphorylation-dependent disruption of their binding to eIF4E. Regulation of protein production through these gene products have been implicated in cell proliferation, cell differentiation and viral infection. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Deamidated asparagine (size 0) in uniprot entity 4EBP2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11922532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4EBP2	NM_004096.5	c.306C>A	p.Asn102Lys	missense_variant	Exon 2 of 3	ENST00000373218.5	NP_004087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4EBP2	ENST00000373218.5	c.306C>A	p.Asn102Lys	missense_variant	Exon 2 of 3	1	NM_004096.5	ENSP00000362314.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456540 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 724456

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

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

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.306C>A (p.N102K) alteration is located in exon 2 (coding exon 2) of the EIF4EBP2 gene. This alteration results from a C to A substitution at nucleotide position 306, causing the asparagine (N) at amino acid position 102 to be replaced by a lysine (K). 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	Benign	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.38
MutPred		0.40		Gain of ubiquitination at N102 (P = 0.0109);
MVP		0.30
MPC		0.58
ClinPred		0.76	D
GERP RS		5.3
Varity_R		0.21
gMVP		0.59

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: rs753546022; hg19: chr10-72179830;