2-27364399-G-A

Variant names:

• chr2-27364399-G-A
• rs41288827
• ENST00000451130.6:c.*1C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000451130.6(EIF2B4):​c.*1C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,786 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.015 (191 hom.)
• Consequence: EIF2B4 ENST00000451130.6 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.657

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-27364399-G-A is Benign according to our data. Variant chr2-27364399-G-A is described in ClinVar as [Benign]. Clinvar id is 335531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1535/152166) while in subpopulation NFE AF= 0.0175 (1188/67996). AF 95% confidence interval is 0.0166. There are 12 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B4	NM_001034116.2	c.*1C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000347454.9	NP_001029288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454	c.*1C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_001034116.2	ENSP00000233552.6

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1535 AN: 152048 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.0107 AC: 2683 AN: 250244 Hom.: 15 AF XY: 0.0108 AC XY: 1466 AN XY: 135416

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00393

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0150 AC: 21943 AN: 1461620 Hom.: 191 Cov.: 32 AF XY: 0.0148 AC XY: 10740 AN XY: 727098

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00426

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0101 AC: 1535 AN: 152166 Hom.: 12 Cov.: 33 AF XY: 0.00907 AC XY: 675 AN XY: 74384

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00439

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.0140 Hom.: 9

Bravo AF: 0.00980

EpiCase AF: 0.0165

EpiControl AF: 0.0157

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EIF2B4-related disorder Benign:1

Sep 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Vanishing white matter disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41288827; hg19: chr2-27587266;