rs78599355

Variant names:

• chr2-27367171-G-C
• rs78599355
• NM_001034116.2:c.916C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-27367171-G-C
• chr2-27367171-G-T
• chr2-27367171-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034116.2(EIF2B4):​c.916C>G​(p.Arg306Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,614,070 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R306R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (41 hom., cov: 32)
  • Exomes 𝑓: 0.024 (498 hom.)
• Consequence: EIF2B4 NM_001034116.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.641
• Publications: 18 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]

GTF3C2-AS2 (HGNC:55699): (GTF3C2 antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006406039).
• BP6: Variant 2-27367171-G-C is Benign according to our data. Variant chr2-27367171-G-C is described in ClinVar as Benign. ClinVar VariationId is 128990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2520/152246) while in subpopulation NFE AF = 0.0258 (1757/68026). AF 95% confidence interval is 0.0248. There are 41 homozygotes in GnomAd4. There are 1200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034116.2. 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.916C>G	p.Arg306Gly	missense	Exon 10 of 13	NP_001029288.1	Q9UI10-1
	EIF2B4	NM_001318965.2		c.979C>G	p.Arg327Gly	missense	Exon 9 of 12	NP_001305894.1	E7ERK9
	EIF2B4	NM_172195.4		c.976C>G	p.Arg326Gly	missense	Exon 9 of 12	NP_751945.2	Q9UI10-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.916C>G	p.Arg306Gly	missense	Exon 10 of 13	ENSP00000233552.6	Q9UI10-1
	EIF2B4	ENST00000451130.6	TSL:1	c.976C>G	p.Arg326Gly	missense	Exon 9 of 12	ENSP00000394869.2	Q9UI10-2
	EIF2B4	ENST00000445933.6	TSL:1	c.913C>G	p.Arg305Gly	missense	Exon 10 of 13	ENSP00000394397.2	Q9UI10-3

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2519 AN: 152128 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0346

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0156 AC: 3920 AN: 251476 AF XY: 0.0151

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0338

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0237 AC: 34590 AN: 1461824 Hom.: 498 Cov.: 34 AF XY: 0.0228 AC XY: 16566 AN XY: 727218

African (AFR) AF: 0.00332 AC: 111 AN: 33480

American (AMR) AF: 0.00626 AC: 280 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00941 AC: 246 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86232

European-Finnish (FIN) AF: 0.0353 AC: 1888 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0275 AC: 30617 AN: 1111982

Other (OTH) AF: 0.0205 AC: 1240 AN: 60396

GnomAD4 genome AF: 0.0166 AC: 2520 AN: 152246 Hom.: 41 Cov.: 32 AF XY: 0.0161 AC XY: 1200 AN XY: 74444

African (AFR) AF: 0.00460 AC: 191 AN: 41538

American (AMR) AF: 0.00792 AC: 121 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.0346 AC: 367 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1757 AN: 68026

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.0201 Hom.: 33

Bravo AF: 0.0137

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0258 AC: 222

ExAC AF: 0.0152 AC: 1843

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0217

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.64
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Benign	0.11	T
Sift4G	Benign	0.37	T
Polyphen		0.0090	B
Vest4		0.14
MPC		0.45
ClinPred		0.0042	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.41
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs78599355; hg19: chr2-27590038; COSMIC: COSV52007864; COSMIC: COSV52007864;