chr12-123621292-T-C

Variant names:

• chr12-123621292-T-C
• rs9919
• NM_001414.4:c.*464A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001414.4(EIF2B1):​c.*464A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 255,610 control chromosomes in the GnomAD database, including 19,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13808 hom., cov: 30)
  • Exomes 𝑓: 0.31 (5949 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60
• Publications: 12 publications found

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]

EIF2B1 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-123621292-T-C is Benign according to our data. Variant chr12-123621292-T-C is described in ClinVar as Benign. ClinVar VariationId is 307518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414.4. 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
	EIF2B1	NM_001414.4	MANE Select	c.*464A>G		3_prime_UTR	Exon 9 of 9	NP_001405.1	Q14232-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	ENST00000424014.7	TSL:1 MANE Select	c.*464A>G		3_prime_UTR	Exon 9 of 9	ENSP00000416250.2	Q14232-1
	EIF2B1	ENST00000929734.1		c.*464A>G		3_prime_UTR	Exon 10 of 10	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.*464A>G		3_prime_UTR	Exon 10 of 10	ENSP00000527269.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60373 AN: 152090 Hom.: 13775 Cov.: 30

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.375

GnomAD4 exome AF: 0.313 AC: 32390 AN: 103402 Hom.: 5949 Cov.: 0 AF XY: 0.320 AC XY: 17537 AN XY: 54722

African (AFR) AF: 0.618 AC: 1775 AN: 2870

American (AMR) AF: 0.227 AC: 1011 AN: 4450

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 696 AN: 2458

East Asian (EAS) AF: 0.0944 AC: 452 AN: 4788

South Asian (SAS) AF: 0.398 AC: 6607 AN: 16600

European-Finnish (FIN) AF: 0.214 AC: 1142 AN: 5340

Middle Eastern (MID) AF: 0.363 AC: 141 AN: 388

European-Non Finnish (NFE) AF: 0.309 AC: 18920 AN: 61198

Other (OTH) AF: 0.310 AC: 1646 AN: 5310

GnomAD4 genome AF: 0.397 AC: 60460 AN: 152208 Hom.: 13808 Cov.: 30 AF XY: 0.393 AC XY: 29236 AN XY: 74410

African (AFR) AF: 0.623 AC: 25877 AN: 41514

American (AMR) AF: 0.302 AC: 4612 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3468

East Asian (EAS) AF: 0.106 AC: 548 AN: 5188

South Asian (SAS) AF: 0.402 AC: 1937 AN: 4822

European-Finnish (FIN) AF: 0.239 AC: 2539 AN: 10606

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22500 AN: 68006

Other (OTH) AF: 0.378 AC: 798 AN: 2110

Alfa AF: 0.351 Hom.: 3913

Bravo AF: 0.406

Asia WGS AF: 0.286 AC: 995 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.047
DANN	Benign	0.43
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs9919; hg19: chr12-124105839;