NM_014239.4:c.254T>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3PP3PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV002240572: Experimental studies have shown that this missense change affects EIF2B2 function (PMID:21484434)." and additional evidence is available in ClinVar.

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:7

Conservation

PhyloP100: 7.95

Publications

13 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: Illumina, Genomics England PanelApp
leukoencephalopathy with vanishing white matter 2
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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

new If you want to explore the variant's impact on the transcript NM_014239.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002240572: Experimental studies have shown that this missense change affects EIF2B2 function (PMID: 21484434).; SCV005416663: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV003928390: showing the variant results in ~80% of normal GDP/GTP exchange activity (Matsukawa_2011).

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B2	NM_014239.4	MANE Select	c.254T>A	p.Val85Glu	missense	Exon 2 of 8	NP_055054.1	Q53XC2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2B2	ENST00000266126.10	TSL:1 MANE Select	c.254T>A	p.Val85Glu	missense	Exon 2 of 8	ENSP00000266126.5	P49770
EIF2B2	ENST00000932124.1		c.254T>A	p.Val85Glu	missense	Exon 2 of 8	ENSP00000602183.1
EIF2B2	ENST00000932126.1		c.254T>A	p.Val85Glu	missense	Exon 2 of 8	ENSP00000602185.1

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

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukoencephalopathy with vanishing white matter 2 (4)

Abnormality of the nervous system (1)

not provided (1)

Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over