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. The variant received -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
• Publications: 3 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 -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 VariationId 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.

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.*2156T>G		3_prime_UTR	Exon 9 of 9	NP_001077083.1	Q5JPH6-1
	EARS2	NR_003501.2		n.3642T>G		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.*2156T>G		3_prime_UTR	Exon 9 of 9	ENSP00000395196.2	Q5JPH6-1
	EARS2	ENST00000674054.1		n.*2063T>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000501251.1	Q5JPH6-1
	EARS2	ENST00000674054.1		n.*2063T>G		3_prime_UTR	Exon 10 of 10	ENSP00000501251.1	Q5JPH6-1

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

African (AFR) AF: 0.204 AC: 393 AN: 1924

American (AMR) AF: 0.0687 AC: 251 AN: 3654

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 92 AN: 1148

East Asian (EAS) AF: 0.0184 AC: 68 AN: 3688

South Asian (SAS) AF: 0.0557 AC: 422 AN: 7570

European-Finnish (FIN) AF: 0.0269 AC: 43 AN: 1596

Middle Eastern (MID) AF: 0.0435 AC: 6 AN: 138

European-Non Finnish (NFE) AF: 0.0222 AC: 631 AN: 28448

Other (OTH) AF: 0.0422 AC: 96 AN: 2276

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

African (AFR) AF: 0.190 AC: 7893 AN: 41482

American (AMR) AF: 0.0951 AC: 1452 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 313 AN: 3468

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5186

South Asian (SAS) AF: 0.0580 AC: 280 AN: 4828

European-Finnish (FIN) AF: 0.0260 AC: 276 AN: 10600

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0287 AC: 1949 AN: 68020

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0561 Hom.: 235

Bravo AF: 0.0921

Asia WGS AF: 0.0760 AC: 266 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.86
PhyloP100		0.76
PromoterAI		0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs13334957; hg19: chr16-23533536;