16-23535037-T-G

Variant names:

• chr16-23535037-T-G
• rs878853014
• NM_001083614.2:c.809A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083614.2(EARS2):​c.809A>C​(p.His270Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H270R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440
• 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
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2613718).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EARS2	NM_001083614.2	MANE Select	c.809A>C	p.His270Pro	missense	Exon 4 of 9	NP_001077083.1
	EARS2	NM_001308211.1		c.809A>C	p.His270Pro	missense	Exon 4 of 8	NP_001295140.1
	EARS2	NR_003501.2		n.816A>C		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EARS2	ENST00000449606.7	TSL:1 MANE Select	c.809A>C	p.His270Pro	missense	Exon 4 of 9	ENSP00000395196.2
	EARS2	ENST00000563232.1	TSL:1	c.809A>C	p.His270Pro	missense	Exon 4 of 8	ENSP00000456218.1
	EARS2	ENST00000564987.1	TSL:1	n.433A>C		non_coding_transcript_exon	Exon 3 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.33
DANN	Benign	0.67
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.044
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.095
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Polyphen		0.040	B
Vest4		0.32
MutPred		0.53		Gain of glycosylation at H270 (P = 0.0234)
MVP		0.21
MPC		0.37
ClinPred		0.20	T
GERP RS		-8.3
Varity_R		0.45
gMVP		0.88

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: rs878853014; hg19: chr16-23546358;