2-206162090-C-A

Variant names:

• chr2-206162090-C-A
• rs1576016842
• NM_001959.4:c.383C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001959.4(EEF1B2):​c.383C>A​(p.Ser128*) variant causes a stop gained change. 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EEF1B2 NM_001959.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.87

Genes affected

EEF1B2 (HGNC:3208): (eukaryotic translation elongation factor 1 beta 2) This gene encodes a translation elongation factor. The protein is a guanine nucleotide exchange factor involved in the transfer of aminoacylated tRNAs to the ribosome. Alternative splicing results in three transcript variants which differ only in the 5' UTR. [provided by RefSeq, Jul 2008]

SNORA41 (HGNC:32634): (small nucleolar RNA, H/ACA box 41)

SNORD51 (HGNC:10201): (small nucleolar RNA, C/D box 51)

snoZ196 (HGNC:):

ACMG classification

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 2-206162090-C-A is Pathogenic according to our data. Variant chr2-206162090-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 689450.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EEF1B2	NM_001959.4	c.383C>A	p.Ser128*	stop_gained	Exon 4 of 6	ENST00000392222.7	NP_001950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EEF1B2	ENST00000392222.7	c.383C>A	p.Ser128*	stop_gained	Exon 4 of 6	1	NM_001959.4	ENSP00000376056.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizure;C2237142:Moderate global developmental delay;C3714756:Intellectual disability Pathogenic:1

Aug 05, 2019

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A first LoF variant was reported in one family with autosomal recessive intellectual disabilities (Najmabadi et al, 2011). The NM_001959.3:c.383C>A, NP_001950.1:p.(Ser128*) variant segregates in the sibship, and is absent in general population alleles in gnomAD ascertained by July 2019. It is a LoF variant in a gene where another LoF variant has been supposed to induce similar symptoms. Moreover, there are multiple lines of computational evidence that support a deleterious effect on the gene or gene product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.41
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1576016842; hg19: chr2-207026814;