rs78170695

Variant names:

• chr12-123630119-G-A
• rs78170695
• NM_001414.4:c.369+50C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001414.4(EIF2B1):​c.369+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,538,694 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: EIF2B1 NM_001414.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.118
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-123630119-G-A is Benign according to our data. Variant chr12-123630119-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 258090.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1662/152208) while in subpopulation AFR AF = 0.0378 (1572/41538). AF 95% confidence interval is 0.0363. There are 39 homozygotes in GnomAd4. There are 788 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

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.369+50C>T		intron	N/A	NP_001405.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	ENST00000424014.7	TSL:1 MANE Select	c.369+50C>T		intron	N/A	ENSP00000416250.2
	EIF2B1	ENST00000929734.1		c.369+50C>T		intron	N/A	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.369+50C>T		intron	N/A	ENSP00000527269.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1653 AN: 152090 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00296 AC: 728 AN: 245864 AF XY: 0.00219

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.000504

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00116 AC: 1612 AN: 1386486 Hom.: 22 Cov.: 25 AF XY: 0.00101 AC XY: 702 AN XY: 693978

African (AFR) AF: 0.0366 AC: 1171 AN: 31952

American (AMR) AF: 0.00199 AC: 89 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.000507 AC: 13 AN: 25666

East Asian (EAS) AF: 0.00 AC: 0 AN: 39386

South Asian (SAS) AF: 0.0000707 AC: 6 AN: 84820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50778

Middle Eastern (MID) AF: 0.00265 AC: 15 AN: 5652

European-Non Finnish (NFE) AF: 0.000171 AC: 179 AN: 1045570

Other (OTH) AF: 0.00239 AC: 139 AN: 58050

GnomAD4 genome AF: 0.0109 AC: 1662 AN: 152208 Hom.: 39 Cov.: 32 AF XY: 0.0106 AC XY: 788 AN XY: 74402

African (AFR) AF: 0.0378 AC: 1572 AN: 41538

American (AMR) AF: 0.00367 AC: 56 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00541 Hom.: 8

Bravo AF: 0.0125

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.73
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

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: rs78170695; hg19: chr12-124114666;