rs1058065

chr2-27364857-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001034116.2(EIF2B4):c.1233C>T(p.Asn411=) 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:4
• Conservation: PhyloP100: -0.855

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

Verdict is Benign. Variant got -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 id is 95737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27364857-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B4	NM_001034116.2	c.1233C>T	p.Asn411=	synonymous_variant	12/13	ENST00000347454.9
GTF3C2-AS2	NR_183825.1	n.1746-2567G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B4	ENST00000347454.9	c.1233C>T	p.Asn411=	synonymous_variant	12/13	1	NM_001034116.2	P4
GTF3C2-AS2	ENST00000412749.1	n.201-2567G>A		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.0114 AC: 2854 AN: 251352 Hom.: 23 AF XY: 0.0111 AC XY: 1511 AN XY: 135856

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 SAS exome AF: 0.00562

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

Gnomad4 AFR exome AF: 0.00818

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0107

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

Gnomad4 AFR AF: 0.00939

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0144 Hom.: 33

Bravo AF: 0.0109

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Vanishing white matter disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.84
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1058065; hg19: chr2-27587724;