rs397514648

Positions:

chr14-75003365-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_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:5

Conservation

PhyloP100: 7.95

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 links:

EIF2B2 (HGNC:):

EIF2B2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 [Likely_pathogenic]. Clinvar id is 40180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75003365-T-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome 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 gnomad4_exome. There are 27 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B2	NM_014239.4 linkuse as main transcript	c.254T>A	p.Val85Glu	missense_variant	2/8	ENST00000266126.10	NP_055054.1	P49770Q53XC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B2	ENST00000266126.10 linkuse as main transcript	c.254T>A	p.Val85Glu	missense_variant	2/8	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

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251012

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135670

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00136

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000333

AC:

AN:

150034

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73110

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000979

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3_VeryStrong+PS3_Supporting+PP1 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Vanishing white matter disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 17, 2023

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

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

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

Varity_R

0.98

gMVP

0.96

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

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