16-23522928-G-C

Position:

• chr16-23522928-G-C

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.*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

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:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EARS2	NM_001083614.2	c.*1443C>G		3_prime_UTR_variant	9/9	ENST00000449606.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EARS2	ENST00000449606.7	c.*1443C>G		3_prime_UTR_variant	9/9	1	NM_001083614.2	P1
EARS2	ENST00000564987.1	n.2566C>G		non_coding_transcript_exon_variant	9/9	1
EARS2	ENST00000674054.1	c.*1350C>G		3_prime_UTR_variant, NMD_transcript_variant	10/10

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

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.851

Gnomad4 ASJ AF: 0.868

Gnomad4 EAS AF: 0.709

Gnomad4 SAS AF: 0.760

Gnomad4 FIN AF: 0.778

Gnomad4 NFE AF: 0.836

Gnomad4 OTH AF: 0.834

Alfa AF: 0.780 Hom.: 2357

Bravo AF: 0.827

Asia WGS AF: 0.762 AC: 2655 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.92
CADD	Benign	0.17
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6497669; hg19: chr16-23534249;