rs7602534

Variant names:

• chr2-27369556-C-T
• rs7602534
• NM_001034116.2:c.76-7G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001034116.2(EIF2B4):​c.76-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,406 control chromosomes in the GnomAD database, including 125,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13164 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111864 hom.)
• Consequence: EIF2B4 NM_001034116.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003890
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.28
• Publications: 42 publications found

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 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 4

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-27369556-C-T is Benign according to our data. Variant chr2-27369556-C-T is described in ClinVar as [Benign]. Clinvar id is 95738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B4	NM_001034116.2	c.76-7G>A		splice_region_variant, intron_variant	Intron 2 of 12	ENST00000347454.9	NP_001029288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9	c.76-7G>A		splice_region_variant, intron_variant	Intron 2 of 12	1	NM_001034116.2	ENSP00000233552.6

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61985 AN: 151866 Hom.: 13131 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.371

GnomAD2 exomes AF: 0.398 AC: 100015 AN: 251384 AF XY: 0.391

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.386 AC: 564162 AN: 1461422 Hom.: 111864 Cov.: 47 AF XY: 0.385 AC XY: 279597 AN XY: 727030

African (AFR) AF: 0.485 AC: 16226 AN: 33470

American (AMR) AF: 0.543 AC: 24286 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 8700 AN: 26134

East Asian (EAS) AF: 0.131 AC: 5205 AN: 39662

South Asian (SAS) AF: 0.397 AC: 34202 AN: 86256

European-Finnish (FIN) AF: 0.432 AC: 23016 AN: 53330

Middle Eastern (MID) AF: 0.337 AC: 1943 AN: 5768

European-Non Finnish (NFE) AF: 0.385 AC: 427977 AN: 1111690

Other (OTH) AF: 0.374 AC: 22607 AN: 60388

GnomAD4 genome AF: 0.408 AC: 62074 AN: 151984 Hom.: 13164 Cov.: 32 AF XY: 0.408 AC XY: 30333 AN XY: 74304

African (AFR) AF: 0.483 AC: 19990 AN: 41424

American (AMR) AF: 0.450 AC: 6866 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3468

East Asian (EAS) AF: 0.150 AC: 774 AN: 5170

South Asian (SAS) AF: 0.403 AC: 1938 AN: 4812

European-Finnish (FIN) AF: 0.429 AC: 4526 AN: 10560

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.379 AC: 25736 AN: 67964

Other (OTH) AF: 0.375 AC: 794 AN: 2116

Alfa AF: 0.386 Hom.: 52560

Bravo AF: 0.414

Asia WGS AF: 0.339 AC: 1179 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Sep 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28008009) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 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

- -

not specified Benign:2

Dec 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vanishing white matter disease Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		1.3
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7602534; hg19: chr2-27592423; COSMIC: COSV52009209; COSMIC: COSV52009209;