16-23535056-G-C

Variant names:

• chr16-23535056-G-C
• rs1555503379
• NM_001083614.2:c.790C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083614.2(EARS2):​c.790C>G​(p.Leu264Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L264L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14
• 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]

EARS2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.790C>G	p.Leu264Val	missense	Exon 4 of 9	NP_001077083.1	Q5JPH6-1
	EARS2	NM_001308211.1		c.790C>G	p.Leu264Val	missense	Exon 4 of 8	NP_001295140.1	Q5JPH6-2
	EARS2	NR_003501.2		n.797C>G		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EARS2	ENST00000449606.7	TSL:1 MANE Select	c.790C>G	p.Leu264Val	missense	Exon 4 of 9	ENSP00000395196.2	Q5JPH6-1
	EARS2	ENST00000563232.1	TSL:1	c.790C>G	p.Leu264Val	missense	Exon 4 of 8	ENSP00000456218.1	Q5JPH6-2
	EARS2	ENST00000564987.1	TSL:1	n.414C>G		non_coding_transcript_exon	Exon 3 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723702

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 43656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 85390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5088

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109762

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.50
MutPred		0.83		Gain of helix (P = 0.1736)
MVP		0.67
MPC		0.63
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.48
gMVP		0.81

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: rs1555503379; hg19: chr16-23546377;