12-123626515-C-A

Variant names:

• chr12-123626515-C-A
• rs79606093
• NM_001414.4:c.483-22G>T

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.483-22G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,613,684 control chromosomes in the GnomAD database, including 2,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (1016 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1246 hom.)
• Consequence: EIF2B1 NM_001414.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.98
• Publications: 6 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

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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=-0.87).
• BP6: Variant 12-123626515-C-A is Benign according to our data. Variant chr12-123626515-C-A is described in ClinVar as Benign. ClinVar VariationId is 258091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B1	NM_001414.4	c.483-22G>T		intron_variant	Intron 5 of 8	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014.7	c.483-22G>T		intron_variant	Intron 5 of 8	1	NM_001414.4	ENSP00000416250.2
EIF2B1	ENST00000537073.1	c.*342G>T		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000444183.1
EIF2B1	ENST00000539951.5	c.444-22G>T		intron_variant	Intron 4 of 6	5		ENSP00000438060.1
EIF2B1	ENST00000534960.5	c.415-1653G>T		intron_variant	Intron 4 of 5	5		ENSP00000443172.1

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11064 AN: 152006 Hom.: 1005 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.00671

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0488

GnomAD2 exomes AF: 0.0311 AC: 7807 AN: 251350 AF XY: 0.0285

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.0173

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00814

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0241 AC: 35152 AN: 1461560 Hom.: 1246 Cov.: 31 AF XY: 0.0240 AC XY: 17438 AN XY: 727128

African (AFR) AF: 0.228 AC: 7622 AN: 33468

American (AMR) AF: 0.0192 AC: 857 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 503 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0388 AC: 3344 AN: 86246

European-Finnish (FIN) AF: 0.00861 AC: 460 AN: 53410

Middle Eastern (MID) AF: 0.0401 AC: 231 AN: 5766

European-Non Finnish (NFE) AF: 0.0182 AC: 20240 AN: 1111748

Other (OTH) AF: 0.0314 AC: 1893 AN: 60382

GnomAD4 genome AF: 0.0731 AC: 11115 AN: 152124 Hom.: 1016 Cov.: 32 AF XY: 0.0710 AC XY: 5283 AN XY: 74366

African (AFR) AF: 0.217 AC: 9016 AN: 41470

American (AMR) AF: 0.0350 AC: 534 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4824

European-Finnish (FIN) AF: 0.00671 AC: 71 AN: 10584

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1173 AN: 67998

Other (OTH) AF: 0.0488 AC: 103 AN: 2112

Alfa AF: 0.0402 Hom.: 102

Bravo AF: 0.0821

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.33
DANN	Benign	0.57
PhyloP100		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs79606093; hg19: chr12-124111062; COSMIC: COSV71194128; COSMIC: COSV71194128;