16-23522468-G-GT

Variant names:

• chr16-23522468-G-GT
• rs79556186
• NM_001083614.2:c.*1902dupA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001083614.2(EARS2):​c.*1902dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 147,486 control chromosomes in the GnomAD database, including 101 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.021 (101 hom., cov: 32)
  • Exomes 𝑓: 0.059 (0 hom.)
• Consequence: EARS2 NM_001083614.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646

Genes affected

EARS2 (HGNC:29419): (glutamyl-tRNA synthetase 2, mitochondrial) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of glutamate to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 12 (COXPD12). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

GGA2 (HGNC:16064): (golgi associated, gamma adaptin ear containing, ARF binding protein 2) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EARS2	NM_001083614.2	c.*1902dupA		3_prime_UTR_variant	Exon 9 of 9	ENST00000449606.7	NP_001077083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EARS2	ENST00000449606	c.*1902dupA		3_prime_UTR_variant	Exon 9 of 9	1	NM_001083614.2	ENSP00000395196.2
EARS2	ENST00000674054.1	n.*1809dupA		non_coding_transcript_exon_variant	Exon 10 of 10			ENSP00000501251.1
EARS2	ENST00000674054.1	n.*1809dupA		3_prime_UTR_variant	Exon 10 of 10			ENSP00000501251.1
EARS2	ENST00000564987.1	n.*155dupA		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3155 AN: 147320 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.00940

Gnomad ASJ AF: 0.000877

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.00390

Gnomad FIN AF: 0.000716

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.0171

GnomAD4 exome AF: 0.0588 AC: 4 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0250 AC XY: 1 AN XY: 40

Gnomad4 AMR exome AF: 0.250

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0215 AC: 3165 AN: 147418 Hom.: 101 Cov.: 32 AF XY: 0.0203 AC XY: 1461 AN XY: 71902

Gnomad4 AFR AF: 0.0704

Gnomad4 AMR AF: 0.00939

Gnomad4 ASJ AF: 0.000877

Gnomad4 EAS AF: 0.00138

Gnomad4 SAS AF: 0.00369

Gnomad4 FIN AF: 0.000716

Gnomad4 NFE AF: 0.00158

Gnomad4 OTH AF: 0.0169

Bravo AF: 0.0242

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs79556186; hg19: chr16-23533789;