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:9
• 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: ClinGen, 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	NM_001034116.2	MANE Select	c.76-7G>A		splice_region intron	N/A	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.139-7G>A		splice_region intron	N/A	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.139-7G>A		splice_region intron	N/A	NP_751945.2	Q9UI10-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.76-7G>A		splice_region intron	N/A	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000451130.6	TSL:1	c.139-7G>A		splice_region intron	N/A	ENSP00000394869.2	Q9UI10-2
	EIF2B4	ENST00000445933.6	TSL:1	c.76-7G>A		splice_region intron	N/A	ENSP00000394397.2	Q9UI10-3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Vanishing white matter disease (2)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7602534;

hg19: chr2-27592423;

COSMIC: COSV52009209;

COSMIC: COSV52009209;