chr2-27364580-T-A

Variant names:

• chr2-27364580-T-A
• rs148810263
• NM_001034116.2:c.1392A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001034116.2(EIF2B4):​c.1392A>T​(p.Gln464His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q464Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF2B4 NM_001034116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 3 publications found

Genes affected

EIF2B4 (HGNC:3260): (eukaryotic translation initiation factor 2B subunit delta) Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GTF3C2-AS2 (HGNC:55699): (GTF3C2 antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001034116.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123487055).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	NM_001034116.2	MANE Select	c.1392A>T	p.Gln464His	missense	Exon 13 of 13	NP_001029288.1
	EIF2B4	NM_001318965.2		c.1455A>T	p.Gln485His	missense	Exon 12 of 12	NP_001305894.1
	EIF2B4	NM_172195.4		c.1452A>T	p.Gln484His	missense	Exon 12 of 12	NP_751945.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.1392A>T	p.Gln464His	missense	Exon 13 of 13	ENSP00000233552.6
	EIF2B4	ENST00000451130.6	TSL:1	c.1452A>T	p.Gln484His	missense	Exon 12 of 12	ENSP00000394869.2
	EIF2B4	ENST00000445933.6	TSL:1	c.1389A>T	p.Gln463His	missense	Exon 13 of 13	ENSP00000394397.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.042
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.18
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.38		Loss of sheet (P = 0.1158)
MVP		0.47
MPC		0.49
ClinPred		0.21	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.63
Mutation Taster		=66/34	polymorphism

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: rs148810263; hg19: chr2-27587447;