rs41288827

Variant names:

• chr2-27364399-G-A
• rs41288827
• ENST00000451130.6:c.*1C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-27364399-G-A
• chr2-27364399-G-C
• chr2-27364399-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000451130.6(EIF2B4):​c.*1C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,786 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.015 (191 hom.)
• Consequence: EIF2B4 ENST00000451130.6 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.657
• Publications: 9 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=-0.83).
• BP6: Variant 2-27364399-G-A is Benign according to our data. Variant chr2-27364399-G-A is described in ClinVar as Benign. ClinVar VariationId is 335531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1535/152166) while in subpopulation NFE AF = 0.0175 (1188/67996). AF 95% confidence interval is 0.0166. There are 12 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000451130.6. 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.*1C>T		3_prime_UTR	Exon 13 of 13	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.*1C>T		3_prime_UTR	Exon 12 of 12	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.*1C>T		3_prime_UTR	Exon 12 of 12	NP_751945.2	Q9UI10-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000451130.6	TSL:1	c.*1C>T		splice_region	Exon 12 of 12	ENSP00000394869.2	Q9UI10-2
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.*1C>T		3_prime_UTR	Exon 13 of 13	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000451130.6	TSL:1	c.*1C>T		3_prime_UTR	Exon 12 of 12	ENSP00000394869.2	Q9UI10-2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1535 AN: 152048 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.0107 AC: 2683 AN: 250244 AF XY: 0.0108

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0150 AC: 21943 AN: 1461620 Hom.: 191 Cov.: 32 AF XY: 0.0148 AC XY: 10740 AN XY: 727098

African (AFR) AF: 0.00230 AC: 77 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26128

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39696

South Asian (SAS) AF: 0.00426 AC: 367 AN: 86240

European-Finnish (FIN) AF: 0.0145 AC: 773 AN: 53310

Middle Eastern (MID) AF: 0.00972 AC: 56 AN: 5764

European-Non Finnish (NFE) AF: 0.0177 AC: 19707 AN: 1111908

Other (OTH) AF: 0.0129 AC: 778 AN: 60388

GnomAD4 genome AF: 0.0101 AC: 1535 AN: 152166 Hom.: 12 Cov.: 33 AF XY: 0.00907 AC XY: 675 AN XY: 74384

African (AFR) AF: 0.00301 AC: 125 AN: 41514

American (AMR) AF: 0.00439 AC: 67 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4816

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1188 AN: 67996

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.0140 Hom.: 9

Bravo AF: 0.00980

EpiCase AF: 0.0165

EpiControl AF: 0.0157

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	EIF2B4-related disorder (1)
-	-	1	not provided (1)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.66
PhyloP100		-0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41288827; hg19: chr2-27587266;