chr12-123630210-T-C

Variant names:

• chr12-123630210-T-C
• rs863225050
• NM_001414.4:c.328A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001414.4(EIF2B1):​c.328A>G​(p.Lys110Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B1 NM_001414.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 12-123630210-T-C is Pathogenic according to our data. Variant chr12-123630210-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 217279.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B1	NM_001414.4	c.328A>G	p.Lys110Glu	missense_variant	Exon 4 of 9	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014.7	c.328A>G	p.Lys110Glu	missense_variant	Exon 4 of 9	1	NM_001414.4	ENSP00000416250.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vanishing white matter disease Pathogenic:1

Jan 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.3	M;.;M
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.037	D;D;D
Sift4G	Uncertain	0.048	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.88
MutPred		0.62		Loss of MoRF binding (P = 0.0037);.;Loss of MoRF binding (P = 0.0037);
MVP		0.99
MPC		2.6
ClinPred		0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.78
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225050; hg19: chr12-124114757;