2-27367171-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034116.2(EIF2B4):c.916C>G(p.Arg306Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,614,070 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 41 hom., cov: 32)

Exomes 𝑓: 0.024 ( 498 hom. )

Consequence

EIF2B4
NM_001034116.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.641

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:

GTF3C2-AS2 (HGNC:55699): (GTF3C2 antisense RNA 2)

GTF3C2-AS2 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 (MetaRNN=0.006406039).

BP6

Variant 2-27367171-G-C is Benign according to our data. Variant chr2-27367171-G-C is described in ClinVar as [Benign]. Clinvar id is 128990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27367171-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2520/152246) while in subpopulation NFE AF= 0.0258 (1757/68026). AF 95% confidence interval is 0.0248. There are 41 homozygotes in gnomad4. There are 1200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B4	NM_001034116.2 link	c.916C>G	p.Arg306Gly	missense_variant	Exon 10 of 13	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.916C>G	p.Arg306Gly	missense_variant	Exon 10 of 13	1	NM_001034116.2	ENSP00000233552.6		Q9UI10-1

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2519

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00461

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0346

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.0156

AC:

3920

AN:

251476

Hom.:

AF XY:

0.0151

AC XY:

2053

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.00552

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00216

Gnomad FIN exome

AF:

0.0338

Gnomad NFE exome

AF:

0.0233

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0237

AC:

34590

AN:

1461824

Hom.:

498

Cov.:

AF XY:

0.0228

AC XY:

16566

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00332

Gnomad4 AMR exome

AF:

0.00626

Gnomad4 ASJ exome

AF:

0.00941

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.0353

Gnomad4 NFE exome

AF:

0.0275

Gnomad4 OTH exome

AF:

0.0205

GnomAD4 genome

AF:

0.0166

AC:

2520

AN:

152246

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1200

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00460

Gnomad4 AMR

AF:

0.00792

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0346

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0137

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0280

AC:

108

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0258

AC:

222

ExAC

AF:

0.0152

AC:

1843

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0238

EpiControl

AF:

0.0217

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Nov 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Vanishing white matter disease

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.069

T;D;.;.;D

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.68

T;T;T;T;T

MetaRNN

Benign

0.0064

T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.0

.;L;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

.;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.11

.;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T

Polyphen

0.0090, 0.14, 0.0040

.;B;B;B;.

Vest4

0.14

MPC

0.45

ClinPred

0.0042

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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