chr16-23522468-G-GT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083614.2. 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
	EARS2	NM_001083614.2	MANE Select	c.*1902dupA		3_prime_UTR	Exon 9 of 9	NP_001077083.1	Q5JPH6-1
	EARS2	NR_003501.2		n.3388dupA		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EARS2	ENST00000449606.7	TSL:1 MANE Select	c.*1902dupA		3_prime_UTR	Exon 9 of 9	ENSP00000395196.2	Q5JPH6-1
	EARS2	ENST00000674054.1		n.*1809dupA		non_coding_transcript_exon	Exon 10 of 10	ENSP00000501251.1	Q5JPH6-1
	EARS2	ENST00000674054.1		n.*1809dupA		3_prime_UTR	Exon 10 of 10	ENSP00000501251.1	Q5JPH6-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0517 AC: 3 AN: 58

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0704 AC: 2837 AN: 40316

American (AMR) AF: 0.00939 AC: 137 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.000877 AC: 3 AN: 3420

East Asian (EAS) AF: 0.00138 AC: 7 AN: 5070

South Asian (SAS) AF: 0.00369 AC: 17 AN: 4608

European-Finnish (FIN) AF: 0.000716 AC: 7 AN: 9778

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00158 AC: 105 AN: 66428

Other (OTH) AF: 0.0169 AC: 34 AN: 2014

Alfa AF: 0.000221 Hom.: 0

Bravo AF: 0.0242

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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: rs79556186; hg19: chr16-23533789; COSMIC: COSV71942965; COSMIC: COSV71942965;