16-23534897-C-T

Variant names:

• chr16-23534897-C-T
• rs746838793
• NM_001083614.2:c.949G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_001083614.2(EARS2):​c.949G>A​(p.Gly317Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G317C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53
• Publications: 5 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
• leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-23534897-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 318550.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 16-23534897-C-T is Pathogenic according to our data. Variant chr16-23534897-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 426388.Status of the report is criteria_provided_single_submitter, 1 stars.

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.949G>A	p.Gly317Ser	missense	Exon 4 of 9	NP_001077083.1
	EARS2	NM_001308211.1		c.949G>A	p.Gly317Ser	missense	Exon 4 of 8	NP_001295140.1
	EARS2	NR_003501.2		n.956G>A		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.949G>A	p.Gly317Ser	missense	Exon 4 of 9	ENSP00000395196.2
	EARS2	ENST00000563232.1	TSL:1	c.949G>A	p.Gly317Ser	missense	Exon 4 of 8	ENSP00000456218.1
	EARS2	ENST00000564987.1	TSL:1	n.573G>A		non_coding_transcript_exon	Exon 3 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422392 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 701616

African (AFR) AF: 0.00 AC: 0 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 42622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23250

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.00 AC: 0 AN: 79086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089202

Other (OTH) AF: 0.00 AC: 0 AN: 58704

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.38	B
Vest4		0.86
MutPred		0.58		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.45
MPC		0.69
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.74

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: rs746838793; hg19: chr16-23546218;