rs41288829

Positions:

chr2-27367799-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001034116.2(EIF2B4):c.729G>A(p.Pro243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,613,502 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 31 hom., cov: 32)

Exomes 𝑓: 0.023 ( 421 hom. )

Consequence

EIF2B4
NM_001034116.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.381

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:):

GTF3C2-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002826959).

BP6

Variant 2-27367799-C-T is Benign according to our data. Variant chr2-27367799-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.381 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2509/152140) while in subpopulation NFE AF= 0.0256 (1740/68006). AF 95% confidence interval is 0.0246. There are 31 homozygotes in gnomad4. There are 1190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B4	NM_001034116.2 linkuse as main transcript	c.729G>A	p.Pro243=	synonymous_variant	8/13	ENST00000347454.9	NP_001029288.1
GTF3C2-AS2	NR_183825.1 linkuse as main transcript	n.2121C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9 linkuse as main transcript	c.729G>A	p.Pro243=	synonymous_variant	8/13	1	NM_001034116.2	ENSP00000233552	P4	Q9UI10-1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2512

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00474

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.0256

Gnomad OTH

AF:

0.0240

GnomAD3 exomes

AF:

0.0169

AC:

4249

AN:

251454

Hom.:

AF XY:

0.0169

AC XY:

2294

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00601

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.0251

Gnomad OTH exome

AF:

0.0213

GnomAD4 exome

AF:

0.0227

AC:

33192

AN:

1461362

Hom.:

421

Cov.:

AF XY:

0.0224

AC XY:

16251

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0186

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00599

Gnomad4 FIN exome

AF:

0.0202

Gnomad4 NFE exome

AF:

0.0261

Gnomad4 OTH exome

AF:

0.0212

GnomAD4 genome

AF:

0.0165

AC:

2509

AN:

152140

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1190

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00472

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.0256

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0215

Hom.:

Bravo

AF:

0.0163

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0248

AC:

213

ExAC

AF:

0.0169

AC:

2050

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0262

EpiControl

AF:

0.0240

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Vanishing white matter disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.1

DANN

Benign

0.71

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0028

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.15

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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