2-27364857-G-A

Variant names:

• chr2-27364857-G-A
• rs1058065
• NM_001034116.2:c.1233C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001034116.2(EIF2B4):​c.1233C>T​(p.Asn411Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,102 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (186 hom.)
• Consequence: EIF2B4 NM_001034116.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.855
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-27364857-G-A is Benign according to our data. Variant chr2-27364857-G-A is described in ClinVar as Benign. ClinVar VariationId is 95737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.855 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1803/152244) while in subpopulation NFE AF = 0.0155 (1051/68022). AF 95% confidence interval is 0.0147. There are 15 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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.1233C>T	p.Asn411Asn	synonymous	Exon 12 of 13	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.1296C>T	p.Asn432Asn	synonymous	Exon 11 of 12	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.1293C>T	p.Asn431Asn	synonymous	Exon 11 of 12	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.1233C>T	p.Asn411Asn	synonymous	Exon 12 of 13	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000451130.6	TSL:1	c.1293C>T	p.Asn431Asn	synonymous	Exon 11 of 12	ENSP00000394869.2	Q9UI10-2
	EIF2B4	ENST00000445933.6	TSL:1	c.1230C>T	p.Asn410Asn	synonymous	Exon 12 of 13	ENSP00000394397.2	Q9UI10-3

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1804 AN: 152126 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0114 AC: 2854 AN: 251352 AF XY: 0.0111

Gnomad AFR exome AF: 0.00942

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0144 AC: 21029 AN: 1461858 Hom.: 186 Cov.: 33 AF XY: 0.0140 AC XY: 10180 AN XY: 727220

African (AFR) AF: 0.00818 AC: 274 AN: 33480

American (AMR) AF: 0.00698 AC: 312 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00546 AC: 471 AN: 86254

European-Finnish (FIN) AF: 0.0157 AC: 840 AN: 53410

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18449 AN: 1111998

Other (OTH) AF: 0.0107 AC: 648 AN: 60396

GnomAD4 genome AF: 0.0118 AC: 1803 AN: 152244 Hom.: 15 Cov.: 32 AF XY: 0.0117 AC XY: 871 AN XY: 74438

African (AFR) AF: 0.00939 AC: 390 AN: 41534

American (AMR) AF: 0.0100 AC: 153 AN: 15282

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4818

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1051 AN: 68022

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0143 Hom.: 56

Bravo AF: 0.0109

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.84
DANN	Benign	0.81
PhyloP100		-0.85
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)		0.010		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: rs1058065; hg19: chr2-27587724;