rs587777052

Positions:

• chr19-3978099-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001961.4(EEF2):​c.1787C>A​(p.Pro596His) 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EEF2 NM_001961.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.94

Genes affected

EEF2 (HGNC:3214): (eukaryotic translation elongation factor 2) This gene encodes a member of the GTP-binding translation elongation factor family. This protein is an essential factor for protein synthesis. It promotes the GTP-dependent translocation of the nascent protein chain from the A-site to the P-site of the ribosome. This protein is completely inactivated by EF-2 kinase phosporylation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EEF2. . Gene score misZ 4.8778 (greater than the threshold 3.09). Trascript score misZ 3.5943 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 26.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 19-3978099-G-T is Pathogenic according to our data. Variant chr19-3978099-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 66077.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEF2	NM_001961.4	c.1787C>A	p.Pro596His	missense_variant	12/15	ENST00000309311.7	NP_001952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEF2	ENST00000309311.7	c.1787C>A	p.Pro596His	missense_variant	12/15	5	NM_001961.4	ENSP00000307940	P1
EEF2	ENST00000600794.1	c.38C>A	p.Pro13His	missense_variant	1/2	3		ENSP00000471265
EEF2	ENST00000596417.1	n.205C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 677114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 26 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2012

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 06, 2019

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease in affected and unaffected individuals from a single family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	4.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.36		Loss of glycosylation at P596 (P = 0.0402);
MVP		0.67
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777052; hg19: chr19-3978097;