12-123621330-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001414.4(EIF2B1):c.*426G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00917 in 284,220 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (60 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.85

Genes affected

EIF2B1 (HGNC:3257): (eukaryotic translation initiation factor 2B subunit alpha) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-123621330-C-G is Benign according to our data. Variant chr12-123621330-C-G is described in ClinVar as [Benign]. Clinvar id is 307519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B1	NM_001414.4	c.*426G>C		3_prime_UTR_variant	9/9	ENST00000424014.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B1	ENST00000424014.7	c.*426G>C		3_prime_UTR_variant	9/9	1	NM_001414.4	P1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2309 AN: 152182 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00199 AC: 263 AN: 131920 Hom.: 6 Cov.: 0 AF XY: 0.00160 AC XY: 113 AN XY: 70752

Gnomad4 AFR exome AF: 0.0577

Gnomad4 AMR exome AF: 0.00366

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000260

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.0154 AC: 2344 AN: 152300 Hom.: 60 Cov.: 33 AF XY: 0.0145 AC XY: 1080 AN XY: 74466

Gnomad4 AFR AF: 0.0531

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0130 Hom.: 6

Bravo AF: 0.0177

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.4
Dann	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs113041500; hg19: chr12-124105877;