20-63488306-CCGCCTTCTG-CCGCCTTCTGCGCCTTCTG

Variant names:

• chr20-63488306-C-CCGCCTTCTG
• rs879255373
• NM_001958.5:c.1375_1383dupCAGAAGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001958.5(EEF1A2):​c.1375_1383dupCAGAAGGCG​(p.Ala461_Gly462insGlnLysAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,385,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A461A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: EEF1A2 NM_001958.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.744
• Publications: 0 publications found

Genes affected

EEF1A2 (HGNC:3192): (eukaryotic translation elongation factor 1 alpha 2) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 2) is expressed in brain, heart and skeletal muscle, and the other isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas. This gene may be critical in the development of ovarian cancer. [provided by RefSeq, Mar 2014]

EEF1A2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 33

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001958.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001958.5. 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
	EEF1A2	NM_001958.5	MANE Select	c.1375_1383dupCAGAAGGCG	p.Ala461_Gly462insGlnLysAla	conservative_inframe_insertion	Exon 8 of 8	NP_001949.1	Q05639

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEF1A2	ENST00000217182.6	TSL:1 MANE Select	c.1375_1383dupCAGAAGGCG	p.Ala461_Gly462insGlnLysAla	conservative_inframe_insertion	Exon 8 of 8	ENSP00000217182.3	Q05639
	EEF1A2	ENST00000298049.13	TSL:1	c.1350+25_1350+33dupCAGAAGGCG		intron	N/A	ENSP00000298049.9	A0A2U3TZH3
	EEF1A2	ENST00000961009.1		c.1444_1452dupCAGAAGGCG	p.Ala484_Gly485insGlnLysAla	conservative_inframe_insertion	Exon 9 of 9	ENSP00000631068.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150520 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.10e-7 AC: 1 AN: 1235306 Hom.: 0 Cov.: 33 AF XY: 0.00000165 AC XY: 1 AN XY: 607458

African (AFR) AF: 0.00 AC: 0 AN: 25104

American (AMR) AF: 0.00 AC: 0 AN: 22328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20880

East Asian (EAS) AF: 0.00 AC: 0 AN: 25384

South Asian (SAS) AF: 0.00 AC: 0 AN: 64760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3920

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 993414

Other (OTH) AF: 0.00 AC: 0 AN: 48988

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150520 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73404

African (AFR) AF: 0.0000243 AC: 1 AN: 41132

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67612

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.74
Mutation Taster		=58/42	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs879255373; hg19: chr20-62119659;