14-75003365-T-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBS1_Supporting

The NM_014239.4(EIF2B2):c.254T>A(p.Val85Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

EIF2B2
NM_014239.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.95

Publications

11 publications found

Variant links:

Genes affected

EIF2B2 (HGNC:3258): (eukaryotic translation initiation factor 2B subunit beta) This gene encodes the beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation. [provided by RefSeq, Aug 2011]

EIF2B2 Gene-Disease associations (from GenCC):

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

EIF2B2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

PP5

Variant 14-75003365-T-A is Pathogenic according to our data. Variant chr14-75003365-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000039 (57/1461828) while in subpopulation EAS AF = 0.00136 (54/39700). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAdExome4. There are 27 alleles in the male GnomAdExome4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B2	NM_014239.4 link	c.254T>A	p.Val85Glu	missense_variant	Exon 2 of 8	ENST00000266126.10	NP_055054.1	P49770Q53XC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B2	ENST00000266126.10 link	c.254T>A	p.Val85Glu	missense_variant	Exon 2 of 8	1	NM_014239.4	ENSP00000266126.5		P49770

Frequencies

GnomAD3 genomes

AF:

0.0000333

AC:

AN:

150034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000979

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000717

AC:

AN:

251012

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00136

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111998

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000333

AC:

AN:

150034

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40510

American (AMR)

AF:

0.00

AC:

AN:

15002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000979

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67670

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 2

Pathogenic:3

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 01, 2025

Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NM_014239.4(EIF2B2):c.254T>A variant results in a missense change (p.Val85Glu). This affects a conserved nucleotide and is present with a low frequency (0.0000385) in gnomAD database, with no homozygotes observed. The variant has been reported in individuals with leukoencephalopathy.In silico predictions and advanced protein modeling (Invitae) support a damaging effec. ClinVar classifies this variant as Likely Pathogenic /Pathogenic (Variation ID: 40180). -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM3_VeryStrong+PS3_Supporting+PP1 -

not provided

Pathogenic:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 85 of the EIF2B2 protein (p.Val85Glu). This variant is present in population databases (rs397514648, gnomAD 0.1%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 21484434, 25031760, 25843247, 28041799, 29700822). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40180). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EIF2B2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EIF2B2 function (PMID: 21484434). For these reasons, this variant has been classified as Pathogenic. -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vanishing white matter disease

Pathogenic:1

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EIF2B2 c.254T>A (p.Val85Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251012 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B2 causing Leukoencephalopathy With Vanishing White Matter (7.2e-05 vs 0.00046), allowing no conclusion about variant significance. c.254T>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Leukoencephalopathy With Vanishing White Matter (Matsukawa_2011, Shimada_2015, Lee_2017, Wei_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant results in ~80% of normal GDP/GTP exchange activity (Matsukawa_2011). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.82

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

PhyloP100

8.0

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.77

Gain of disorder (P = 0.0084);

MVP

0.99

MPC

1.7

ClinPred

0.73

GERP RS

5.6

PromoterAI

0.0032

Neutral

(source)

Varity_R

0.98

gMVP

0.96

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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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