16-23522928-G-C

Variant names:

• chr16-23522928-G-C
• rs6497669
• NM_001083614.2:c.*1443C>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.*1443C>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 0.821 in 152,182 control chromosomes in the GnomAD database, including 51,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51421 hom., cov: 32)
  • Exomes 𝑓: 0.70 (2 hom.)
• Consequence: EARS2 NM_001083614.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.89
• Publications: 9 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=-0.92).
• BP6: Variant 16-23522928-G-C is Benign according to our data. Variant chr16-23522928-G-C is described in ClinVar as Benign. ClinVar VariationId is 318518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.838 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.*1443C>G		3_prime_UTR	Exon 9 of 9	NP_001077083.1	Q5JPH6-1
	EARS2	NR_003501.2		n.2929C>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.*1443C>G		3_prime_UTR	Exon 9 of 9	ENSP00000395196.2	Q5JPH6-1
	EARS2	ENST00000564987.1	TSL:1	n.2566C>G		non_coding_transcript_exon	Exon 9 of 9
	EARS2	ENST00000674054.1		n.*1350C>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000501251.1	Q5JPH6-1

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124906 AN: 152054 Hom.: 51396 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.838

GnomAD4 exome AF: 0.700 AC: 7 AN: 10 Hom.: 2 Cov.: 0 AF XY: 0.667 AC XY: 4 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

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: 0.750 AC: 6 AN: 8

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.821 AC: 124979 AN: 152172 Hom.: 51421 Cov.: 32 AF XY: 0.818 AC XY: 60831 AN XY: 74388

African (AFR) AF: 0.813 AC: 33718 AN: 41498

American (AMR) AF: 0.851 AC: 12988 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3011 AN: 3470

East Asian (EAS) AF: 0.709 AC: 3659 AN: 5160

South Asian (SAS) AF: 0.760 AC: 3672 AN: 4830

European-Finnish (FIN) AF: 0.778 AC: 8243 AN: 10598

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.836 AC: 56890 AN: 68026

Other (OTH) AF: 0.834 AC: 1764 AN: 2116

Alfa AF: 0.780 Hom.: 2357

Bravo AF: 0.827

Asia WGS AF: 0.762 AC: 2655 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	-0.92
CADD	Benign	0.17
DANN	Benign	0.49
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6497669; hg19: chr16-23534249;