NM_001034116.2:c.1014-7A>G

Variant names:

• chr2-27366943-T-C
• rs2280737
• NM_001034116.2:c.1014-7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001034116.2(EIF2B4):​c.1014-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,613,664 control chromosomes in the GnomAD database, including 125,907 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 (13339 hom., cov: 32)
  • Exomes 𝑓: 0.39 (112568 hom.)
• Consequence: EIF2B4 NM_001034116.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.513
• Publications: 31 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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-27366943-T-C is Benign according to our data. Variant chr2-27366943-T-C is described in ClinVar as Benign. ClinVar VariationId is 95736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B4	NM_001034116.2	c.1014-7A>G		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000347454.9	NP_001029288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9	c.1014-7A>G		splice_region_variant, intron_variant	Intron 10 of 12	1	NM_001034116.2	ENSP00000233552.6

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62372 AN: 151858 Hom.: 13309 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.400 AC: 100371 AN: 250944 AF XY: 0.393

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.387 AC: 566304 AN: 1461688 Hom.: 112568 Cov.: 49 AF XY: 0.386 AC XY: 280656 AN XY: 727148

African (AFR) AF: 0.487 AC: 16313 AN: 33476

American (AMR) AF: 0.544 AC: 24309 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8969 AN: 26134

East Asian (EAS) AF: 0.141 AC: 5598 AN: 39664

South Asian (SAS) AF: 0.401 AC: 34564 AN: 86242

European-Finnish (FIN) AF: 0.434 AC: 23179 AN: 53378

Middle Eastern (MID) AF: 0.349 AC: 2013 AN: 5768

European-Non Finnish (NFE) AF: 0.385 AC: 428558 AN: 1111908

Other (OTH) AF: 0.378 AC: 22801 AN: 60394

GnomAD4 genome AF: 0.411 AC: 62458 AN: 151976 Hom.: 13339 Cov.: 32 AF XY: 0.411 AC XY: 30498 AN XY: 74276

African (AFR) AF: 0.486 AC: 20124 AN: 41442

American (AMR) AF: 0.449 AC: 6856 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1189 AN: 3470

East Asian (EAS) AF: 0.157 AC: 811 AN: 5168

South Asian (SAS) AF: 0.403 AC: 1943 AN: 4824

European-Finnish (FIN) AF: 0.432 AC: 4551 AN: 10532

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25833 AN: 67950

Other (OTH) AF: 0.373 AC: 787 AN: 2110

Alfa AF: 0.382 Hom.: 16723

Bravo AF: 0.415

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 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

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2014

Eurofins Ntd Llc (ga)

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	-0.86
CADD	Benign	3.6
DANN	Benign	0.41
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs2280737; hg19: chr2-27589810; COSMIC: COSV52011599; COSMIC: COSV52011599;