chr16-23525320-T-G

Variant names:

• chr16-23525320-T-G
• rs137973249
• NM_001083614.2:c.1412A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083614.2(EARS2):​c.1412A>C​(p.Lys471Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,120 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.202
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041161776).
• BP6: Variant 16-23525320-T-G is Benign according to our data. Variant chr16-23525320-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00889 (1354/152246) while in subpopulation AFR AF = 0.0304 (1264/41546). AF 95% confidence interval is 0.029. There are 23 homozygotes in GnomAd4. There are 619 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.1412A>C	p.Lys471Thr	missense	Exon 8 of 9	NP_001077083.1	Q5JPH6-1
	EARS2	NM_001308211.1		c.1412A>C	p.Lys471Thr	missense	Exon 8 of 8	NP_001295140.1	Q5JPH6-2
	EARS2	NR_003501.2		n.1419A>C		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EARS2	ENST00000449606.7	TSL:1 MANE Select	c.1412A>C	p.Lys471Thr	missense	Exon 8 of 9	ENSP00000395196.2	Q5JPH6-1
	EARS2	ENST00000563232.1	TSL:1	c.1412A>C	p.Lys471Thr	missense	Exon 8 of 8	ENSP00000456218.1	Q5JPH6-2
	EARS2	ENST00000564987.1	TSL:1	n.1056A>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152128 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00269 AC: 670 AN: 249494 AF XY: 0.00202

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00112 AC: 1641 AN: 1461874 Hom.: 26 Cov.: 32 AF XY: 0.000985 AC XY: 716 AN XY: 727238

African (AFR) AF: 0.0340 AC: 1139 AN: 33480

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.000199 AC: 221 AN: 1111998

Other (OTH) AF: 0.00232 AC: 140 AN: 60396

GnomAD4 genome AF: 0.00889 AC: 1354 AN: 152246 Hom.: 23 Cov.: 32 AF XY: 0.00831 AC XY: 619 AN XY: 74450

African (AFR) AF: 0.0304 AC: 1264 AN: 41546

American (AMR) AF: 0.00399 AC: 61 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67998

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00357 Hom.: 18

Bravo AF: 0.0107

ESP6500AA AF: 0.0275 AC: 107

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00322 AC: 389

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.20
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.052
Sift	Benign	0.30	T
Sift4G	Benign	0.50	T
Polyphen		0.0040	B
Vest4		0.17
MVP		0.60
MPC		0.20
ClinPred		0.0012	T
GERP RS		2.9
Varity_R		0.046
gMVP		0.24
Mutation Taster		=89/11	polymorphism

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: rs137973249; hg19: chr16-23536641; COSMIC: COSV106116048; COSMIC: COSV106116048;