14-75003012-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014239.4(EIF2B2):c.22G>A(p.Gly8Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G8A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2B2 NM_014239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

Genes affected

EIF2B2 (HGNC:3258): (eukaryotic translation initiation factor 2B subunit beta) This gene encodes the beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13216189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B2	NM_014239.4	c.22G>A	p.Gly8Ser	missense_variant	1/8	ENST00000266126.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B2	ENST00000266126.10	c.22G>A	p.Gly8Ser	missense_variant	1/8	1	NM_014239.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.22G>A (p.G8S) alteration is located in exon 1 (coding exon 1) of the EIF2B2 gene. This alteration results from a G to A substitution at nucleotide position 22, causing the glycine (G) at amino acid position 8 to be replaced by a serine (S). 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	0.085
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	15
Dann	Benign	0.71
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.21
Sift	Benign	0.61	T
Sift4G	Benign	0.65	T
Polyphen		0.0060	B
Vest4		0.15
MutPred		0.22		Gain of phosphorylation at G8 (P = 0.005);
MVP		0.98
MPC		0.44
ClinPred		0.21	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.27

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: rs1239271075; hg19: chr14-75469715;