rs104894427
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_014239.4(EIF2B2):c.547C>T(p.Arg183Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000242 in 1,612,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 28)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
EIF2B2
NM_014239.4 stop_gained
NM_014239.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.88
Genes affected
EIF2B2 (HGNC:3258): (eukaryotic translation initiation factor 2B subunit beta) This gene encodes the beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-75004850-C-T is Pathogenic according to our data. Variant chr14-75004850-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4338.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2B2 | NM_014239.4 | c.547C>T | p.Arg183Ter | stop_gained | 4/8 | ENST00000266126.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2B2 | ENST00000266126.10 | c.547C>T | p.Arg183Ter | stop_gained | 4/8 | 1 | NM_014239.4 | P1 | |
ENST00000554430.1 | n.358G>A | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151164Hom.: 0 Cov.: 28
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251026Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135776
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4338). This premature translational stop signal has been observed in individual(s) with clinical features of leukoencephalopathy with vanishing white matter (PMID: 12707859). This variant is present in population databases (rs104894427, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg183*) in the EIF2B2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EIF2B2 are known to be pathogenic (PMID: 11704758, 12707859). - |
Leukoencephalopathy with vanishing white matter 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2003 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at