chr14-75009191-G-C

Variant names:

• chr14-75009191-G-C
• rs112087431
• NM_014239.4:c.*3G>C

Variant summary

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

The NM_014239.4(EIF2B2):​c.*3G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,784 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (60 hom., cov: 32)
  • Exomes 𝑓: 0.013 (200 hom.)
• Consequence: EIF2B2 NM_014239.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.254
• Publications: 8 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-75009191-G-C is Benign according to our data. Variant chr14-75009191-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 260364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.021 (3201/152102) while in subpopulation AFR AF = 0.0461 (1910/41466). AF 95% confidence interval is 0.0443. There are 60 homozygotes in GnomAd4. There are 1527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

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.*3G>C		3_prime_UTR	Exon 8 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.*3G>C		3_prime_UTR	Exon 8 of 8	ENSP00000266126.5
	EIF2B2	ENST00000556668.1	TSL:2	n.639G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3193 AN: 151986 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0150 AC: 3759 AN: 251416 AF XY: 0.0158

Gnomad AFR exome AF: 0.0435

Gnomad AMR exome AF: 0.00818

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0122

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0130 AC: 19068 AN: 1461682 Hom.: 200 Cov.: 32 AF XY: 0.0137 AC XY: 9949 AN XY: 727166

African (AFR) AF: 0.0477 AC: 1598 AN: 33474

American (AMR) AF: 0.00841 AC: 376 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26132

East Asian (EAS) AF: 0.0101 AC: 402 AN: 39696

South Asian (SAS) AF: 0.0365 AC: 3150 AN: 86222

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53376

Middle Eastern (MID) AF: 0.0251 AC: 145 AN: 5768

European-Non Finnish (NFE) AF: 0.0110 AC: 12277 AN: 1111902

Other (OTH) AF: 0.0152 AC: 918 AN: 60388

GnomAD4 genome AF: 0.0210 AC: 3201 AN: 152102 Hom.: 60 Cov.: 32 AF XY: 0.0205 AC XY: 1527 AN XY: 74348

African (AFR) AF: 0.0461 AC: 1910 AN: 41466

American (AMR) AF: 0.0118 AC: 181 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5172

South Asian (SAS) AF: 0.0415 AC: 200 AN: 4816

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10580

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 758 AN: 68008

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.00811 Hom.: 4

Bravo AF: 0.0220

Asia WGS AF: 0.0290 AC: 99 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Lynch syndrome (1)
-	-	1	not provided (1)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.53
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs112087431; hg19: chr14-75475894;