chr14-75006701-A-T

Variant names:

• chr14-75006701-A-T
• rs113994016
• NM_014239.4:c.818A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_014239.4(EIF2B2):​c.818A>T​(p.Lys273Ile) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K273R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B2 NM_014239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

EIF2B2 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter

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

  Inheritance: AR Classification: STRONG Submitted by: G2P
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258646 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-75006701-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B2	NM_014239.4	MANE Select	c.818A>T	p.Lys273Ile	missense	Exon 6 of 8	NP_055054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B2	ENST00000266126.10	TSL:1 MANE Select	c.818A>T	p.Lys273Ile	missense	Exon 6 of 8	ENSP00000266126.5
	EIF2B2	ENST00000554748.2	TSL:3	c.182A>T	p.Lys61Ile	missense	Exon 2 of 3	ENSP00000452582.2
	EIF2B2	ENST00000553401.5	TSL:5	n.*213A>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000451681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Lys273 amino acid residue in EIF2B2. Other variant(s) that disrupt this residue have been observed in individuals with EIF2B2-related conditions (PMID: 11704758, 22992991), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 273 of the EIF2B2 protein (p.Lys273Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EIF2B2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.73		Loss of methylation at K273 (P = 4e-04)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.96
Mutation Taster		=5/95	disease causing

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: rs113994016; hg19: chr14-75473404;