2-27364361-G-A

Variant names:

• chr2-27364361-G-A
• rs367568951
• NM_001034116.2:c.*39C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001034116.2(EIF2B4):​c.*39C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,598,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: EIF2B4 NM_001034116.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.165
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000407 (62/152266) while in subpopulation AFR AF = 0.000866 (36/41550). AF 95% confidence interval is 0.000642. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	NM_001034116.2	MANE Select	c.*39C>T		3_prime_UTR	Exon 13 of 13	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.*39C>T		3_prime_UTR	Exon 12 of 12	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.*39C>T		3_prime_UTR	Exon 12 of 12	NP_751945.2	Q9UI10-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.*39C>T		3_prime_UTR	Exon 13 of 13	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000945158.1		c.*39C>T		splice_region	Exon 13 of 13	ENSP00000615217.1
	EIF2B4	ENST00000945155.1		c.*39C>T		splice_region	Exon 13 of 13	ENSP00000615214.1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000221 AC: 53 AN: 240188 AF XY: 0.000200

Gnomad AFR exome AF: 0.000721

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000654

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000122 AC: 176 AN: 1446418 Hom.: 0 Cov.: 29 AF XY: 0.000117 AC XY: 84 AN XY: 719732

African (AFR) AF: 0.00130 AC: 43 AN: 33154

American (AMR) AF: 0.0000228 AC: 1 AN: 43842

Ashkenazi Jewish (ASJ) AF: 0.00343 AC: 89 AN: 25960

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 85290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.0000164 AC: 18 AN: 1100468

Other (OTH) AF: 0.000401 AC: 24 AN: 59860

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74456

African (AFR) AF: 0.000866 AC: 36 AN: 41550

American (AMR) AF: 0.000720 AC: 11 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000446

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		-0.17
Mutation Taster		=100/0	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: rs367568951; hg19: chr2-27587228; COSMIC: COSV61456789; COSMIC: COSV61456789;