rs886038381

Variant names:

• chr2-27369959-T-G
• rs886038381
• ENST00000451130.6:c.55A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-27369959-T-G
• chr2-27369959-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001318965.2(EIF2B4):​c.55A>C​(p.Ser19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: EIF2B4 NM_001318965.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.621
• Publications: 0 publications found

Genes affected

EIF2B4 (HGNC:3260): (eukaryotic translation initiation factor 2B subunit delta) Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EIF2B4 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 4

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09447417).
• BP6: Variant 2-27369959-T-G is Benign according to our data. Variant chr2-27369959-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 257182.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318965.2. 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
	EIF2B4	NM_001034116.2	MANE Select	c.32-40A>C		intron	N/A	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.55A>C	p.Ser19Arg	missense	Exon 1 of 12	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.55A>C	p.Ser19Arg	missense	Exon 1 of 12	NP_751945.2	Q9UI10-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000451130.6	TSL:1	c.55A>C	p.Ser19Arg	missense	Exon 1 of 12	ENSP00000394869.2	Q9UI10-2
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.32-40A>C		intron	N/A	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000445933.6	TSL:1	c.32-40A>C		intron	N/A	ENSP00000394397.2	Q9UI10-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 694090

African (AFR) AF: 0.00 AC: 0 AN: 31880

American (AMR) AF: 0.00 AC: 0 AN: 36400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 36222

South Asian (SAS) AF: 0.00 AC: 0 AN: 79664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082928

Other (OTH) AF: 0.0000171 AC: 1 AN: 58310

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.88	T
PhyloP100		0.62
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.16
Sift	Benign	0.043	D
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.18		Loss of phosphorylation at S19 (P = 0.0039)
MVP		0.26
MPC		0.96
ClinPred		0.32	T
GERP RS		1.2
PromoterAI		0.010	Neutral
gMVP		0.15
Mutation Taster		=95/5	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: rs886038381; hg19: chr2-27592826;