rs2280737

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-27366943-T-C
• chr2-27366943-T-A
• chr2-27366943-T-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.

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.1014-7A>G		splice_region intron	N/A	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.1077-7A>G		splice_region intron	N/A	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.1074-7A>G		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.1014-7A>G		splice_region intron	N/A	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000451130.6	TSL:1	c.1074-7A>G		splice_region intron	N/A	ENSP00000394869.2	Q9UI10-2
	EIF2B4	ENST00000445933.6	TSL:1	c.1011-7A>G		splice_region intron	N/A	ENSP00000394397.2	Q9UI10-3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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;