NM_001083614.2:c.*2156T>G

Variant names:

• chr16-23522215-A-C
• rs13334957
• NM_001083614.2:c.*2156T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083614.2(EARS2):​c.*2156T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 202,614 control chromosomes in the GnomAD database, including 986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (902 hom., cov: 32)
  • Exomes 𝑓: 0.040 (84 hom.)
• Consequence: EARS2 NM_001083614.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.761

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-23522215-A-C is Benign according to our data. Variant chr16-23522215-A-C is described in ClinVar as [Benign]. Clinvar id is 318510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EARS2	NM_001083614.2	c.*2156T>G		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.*2156T>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001083614.2	ENSP00000395196.2
EARS2	ENST00000674054.1	n.*2063T>G		non_coding_transcript_exon_variant	Exon 10 of 10			ENSP00000501251.1
EARS2	ENST00000674054.1	n.*2063T>G		3_prime_UTR_variant	Exon 10 of 10			ENSP00000501251.1
GGA2	ENST00000569300.5	c.-415T>G		upstream_gene_variant		4		ENSP00000455331.1

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12419 AN: 152054 Hom.: 898 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.0903

Gnomad EAS AF: 0.0192

Gnomad SAS AF: 0.0586

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0774

GnomAD4 exome AF: 0.0397 AC: 2002 AN: 50442 Hom.: 84 Cov.: 0 AF XY: 0.0412 AC XY: 1124 AN XY: 27286

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.0687

Gnomad4 ASJ exome AF: 0.0801

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.0557

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0422

GnomAD4 genome AF: 0.0819 AC: 12460 AN: 152172 Hom.: 902 Cov.: 32 AF XY: 0.0813 AC XY: 6047 AN XY: 74388

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0951

Gnomad4 ASJ AF: 0.0903

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0580

Gnomad4 FIN AF: 0.0260

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.0776

Alfa AF: 0.0535 Hom.: 192

Bravo AF: 0.0921

Asia WGS AF: 0.0760 AC: 266 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.86

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: rs13334957; hg19: chr16-23533536;