2-27367171-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

18 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 links:

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

GTF3C2-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 128990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

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

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

GnomAD2 exomes

AF:

0.0156

AC:

3920

AN:

251476

AF XY:

0.0151

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 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

African (AFR)

AF:

0.00332

AC:

111

AN:

33480

American (AMR)

AF:

0.00626

AC:

280

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00941

AC:

246

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.00225

AC:

194

AN:

86232

European-Finnish (FIN)

AF:

0.0353

AC:

1888

AN:

53418

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0275

AC:

30617

AN:

1111982

Other (OTH)

AF:

0.0205

AC:

1240

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1941

3883

5824

7766

9707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1172

2344

3516

4688

5860

<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:

0.0166

AC:

2520

AN:

152246

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1200

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00460

AC:

191

AN:

41538

American (AMR)

AF:

0.00792

AC:

121

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00290

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0346

AC:

367

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1757

AN:

68026

Other (OTH)

AF:

0.0142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

248

372

496

620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0201

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

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

- -

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. -

not provided

Benign:3

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 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

- -

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

(source)

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;.;.;.

PhyloP100

0.64

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

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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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