chr2-27366943-T-C

Position:

chr2-27366943-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001034116.2(EIF2B4):c.1014-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,613,664 control chromosomes in the GnomAD database, including 125,907 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13339 hom., cov: 32)

Exomes 𝑓: 0.39 ( 112568 hom. )

Consequence

EIF2B4
NM_001034116.2 splice_region, intron

Scores

Splicing: ADA: 0.00002390

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.513

Variant links:

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 links:

EIF2B4 (HGNC:):

EIF2B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-27366943-T-C is Benign according to our data. Variant chr2-27366943-T-C is described in ClinVar as [Benign]. Clinvar id is 95736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27366943-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B4	NM_001034116.2 linkuse as main transcript	c.1014-7A>G		splice_region_variant, intron_variant		ENST00000347454.9	NP_001029288.1	Q9UI10-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9 linkuse as main transcript	c.1014-7A>G		splice_region_variant, intron_variant		1	NM_001034116.2	ENSP00000233552.6		Q9UI10-1

Frequencies

GnomAD3 genomes

AF:

0.411

AC:

62372

AN:

151858

Hom.:

13309

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.448

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.401

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.380

Gnomad OTH

AF:

0.369

GnomAD3 exomes

AF:

0.400

AC:

100371

AN:

250944

Hom.:

21410

AF XY:

0.393

AC XY:

53274

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.484

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.343

Gnomad EAS exome

AF:

0.154

Gnomad SAS exome

AF:

0.402

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.380

Gnomad OTH exome

AF:

0.391

GnomAD4 exome

AF:

0.387

AC:

566304

AN:

1461688

Hom.:

112568

Cov.:

AF XY:

0.386

AC XY:

280656

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.487

Gnomad4 AMR exome

AF:

0.544

Gnomad4 ASJ exome

AF:

0.343

Gnomad4 EAS exome

AF:

0.141

Gnomad4 SAS exome

AF:

0.401

Gnomad4 FIN exome

AF:

0.434

Gnomad4 NFE exome

AF:

0.385

Gnomad4 OTH exome

AF:

0.378

GnomAD4 genome

AF:

0.411

AC:

62458

AN:

151976

Hom.:

13339

Cov.:

AF XY:

0.411

AC XY:

30498

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.486

Gnomad4 AMR

AF:

0.449

Gnomad4 ASJ

AF:

0.343

Gnomad4 EAS

AF:

0.157

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.432

Gnomad4 NFE

AF:

0.380

Gnomad4 OTH

AF:

0.373

Alfa

AF:

0.376

Hom.:

11887

Bravo

AF:

0.415

Asia WGS

AF:

0.335

AC:

1165

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 28008009) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -

Vanishing white matter disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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 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

-0.86

CADD

Benign

3.6

DANN

Benign

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over