chr2-27364580-T-C

Position:

• chr2-27364580-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001034116.2(EIF2B4):​c.1392A>G​(p.Gln464Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,614,238 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (16 hom.)
• Consequence: EIF2B4 NM_001034116.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0420

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]

EIF2B4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-27364580-T-C is Benign according to our data. Variant chr2-27364580-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 335532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27364580-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.042 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00388 (591/152344) while in subpopulation NFE AF= 0.00463 (315/68032). AF 95% confidence interval is 0.00421. There are 2 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B4	NM_001034116.2	c.1392A>G	p.Gln464Gln	synonymous_variant	13/13	ENST00000347454.9	NP_001029288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9	c.1392A>G	p.Gln464Gln	synonymous_variant	13/13	1	NM_001034116.2	ENSP00000233552.6

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152226 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00395 AC: 993 AN: 251464 Hom.: 2 AF XY: 0.00389 AC XY: 529 AN XY: 135914

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00402 AC: 5875 AN: 1461894 Hom.: 16 Cov.: 32 AF XY: 0.00388 AC XY: 2821 AN XY: 727248

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00589

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152344 Hom.: 2 Cov.: 33 AF XY: 0.00450 AC XY: 335 AN XY: 74504

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00264

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	EIF2B4: BP4, BP7 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 07, 2017

- -

EIF2B4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

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). -

Vanishing white matter disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.0
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148810263; hg19: chr2-27587447;