chr2-27369556-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001034116.2(EIF2B4):c.76-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,406 control chromosomes in the GnomAD database, including 125,028 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 ( 13164 hom., cov: 32)

Exomes 𝑓: 0.39 ( 111864 hom. )

Consequence

EIF2B4
NM_001034116.2 splice_region, intron

Scores

Splicing: ADA: 0.0003890

Clinical Significance

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

Conservation

PhyloP100: 1.28

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

leukoencephalopathy with vanishing white matter 4
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
leukoencephalopathy with vanishing white matter
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
leukoencephalopathy with vanishing white matter 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarioleukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EIF2B4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-27369556-C-T is Benign according to our data. Variant chr2-27369556-C-T is described in ClinVar as [Benign]. Clinvar id is 95738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B4	NM_001034116.2 link	c.76-7G>A		splice_region_variant, intron_variant	Intron 2 of 12	ENST00000347454.9	NP_001029288.1	Q9UI10-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9 link	c.76-7G>A		splice_region_variant, intron_variant	Intron 2 of 12	1	NM_001034116.2	ENSP00000233552.6		Q9UI10-1

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61985

AN:

151866

Hom.:

13131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.483

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.449

Gnomad ASJ

AF:

0.329

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.429

Gnomad MID

AF:

0.363

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.371

GnomAD2 exomes

AF:

0.398

AC:

100015

AN:

251384

AF XY:

0.391

show subpopulations

Gnomad AFR exome

AF:

0.483

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.428

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.386

AC:

564162

AN:

1461422

Hom.:

111864

Cov.:

AF XY:

0.385

AC XY:

279597

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.485

AC:

16226

AN:

33470

American (AMR)

AF:

0.543

AC:

24286

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

8700

AN:

26134

East Asian (EAS)

AF:

0.131

AC:

5205

AN:

39662

South Asian (SAS)

AF:

0.397

AC:

34202

AN:

86256

European-Finnish (FIN)

AF:

0.432

AC:

23016

AN:

53330

Middle Eastern (MID)

AF:

0.337

AC:

1943

AN:

5768

European-Non Finnish (NFE)

AF:

0.385

AC:

427977

AN:

1111690

Other (OTH)

AF:

0.374

AC:

22607

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

20617

41235

61852

82470

103087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13622

27244

40866

54488

68110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.408

AC:

62074

AN:

151984

Hom.:

13164

Cov.:

AF XY:

0.408

AC XY:

30333

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.483

AC:

19990

AN:

41424

American (AMR)

AF:

0.450

AC:

6866

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

1141

AN:

3468

East Asian (EAS)

AF:

0.150

AC:

774

AN:

5170

South Asian (SAS)

AF:

0.403

AC:

1938

AN:

4812

European-Finnish (FIN)

AF:

0.429

AC:

4526

AN:

10560

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.379

AC:

25736

AN:

67964

Other (OTH)

AF:

0.375

AC:

794

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1855

3711

5566

7422

9277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.386

Hom.:

52560

Bravo

AF:

0.414

Asia WGS

AF:

0.339

AC:

1179

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

Sep 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28008009) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Dec 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vanishing white matter disease

Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

1.3

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over