chr11-78566231-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024678.6(NARS2):c.414T>C(p.Tyr138Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,609,114 control chromosomes in the GnomAD database, including 471,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38909 hom., cov: 32)

Exomes 𝑓: 0.77 ( 432967 hom. )

Consequence

NARS2
NM_024678.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0660

Publications

36 publications found

Variant links:

Genes affected

NARS2 (HGNC:26274): (asparaginyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative member of the class II 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 asparagine to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24). [provided by RefSeq, Mar 2015]

NARS2 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 24
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: Illumina
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive 94
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 11-78566231-A-G is Benign according to our data. Variant chr11-78566231-A-G is described in ClinVar as Benign. ClinVar VariationId is 380001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.066 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6 link	c.414T>C	p.Tyr138Tyr	synonymous_variant	Exon 4 of 14	ENST00000281038.10	NP_078954.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10 link	c.414T>C	p.Tyr138Tyr	synonymous_variant	Exon 4 of 14	1	NM_024678.6	ENSP00000281038.5

Frequencies

GnomAD3 genomes

AF:

0.710

AC:

107883

AN:

151956

Hom.:

38897

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.795

Gnomad AMR

AF:

0.668

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.697

Gnomad FIN

AF:

0.677

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.791

Gnomad OTH

AF:

0.713

GnomAD2 exomes

AF:

0.706

AC:

176150

AN:

249416

AF XY:

0.715

show subpopulations

Gnomad AFR exome

AF:

0.617

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.681

Gnomad EAS exome

AF:

0.569

Gnomad FIN exome

AF:

0.691

Gnomad NFE exome

AF:

0.790

Gnomad OTH exome

AF:

0.734

GnomAD4 exome

AF:

0.768

AC:

1118321

AN:

1457040

Hom.:

432967

Cov.:

AF XY:

0.767

AC XY:

555654

AN XY:

724804

show subpopulations

African (AFR)

AF:

0.609

AC:

20310

AN:

33330

American (AMR)

AF:

0.580

AC:

25681

AN:

44314

Ashkenazi Jewish (ASJ)

AF:

0.676

AC:

17595

AN:

26018

East Asian (EAS)

AF:

0.584

AC:

23115

AN:

39586

South Asian (SAS)

AF:

0.684

AC:

58499

AN:

85580

European-Finnish (FIN)

AF:

0.701

AC:

37364

AN:

53272

Middle Eastern (MID)

AF:

0.647

AC:

3721

AN:

5752

European-Non Finnish (NFE)

AF:

0.800

AC:

887289

AN:

1109014

Other (OTH)

AF:

0.744

AC:

44747

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

11143

22285

33428

44570

55713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20636

41272

61908

82544

103180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.710

AC:

107937

AN:

152074

Hom.:

38909

Cov.:

AF XY:

0.703

AC XY:

52292

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.620

AC:

25719

AN:

41456

American (AMR)

AF:

0.668

AC:

10206

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.673

AC:

2337

AN:

3472

East Asian (EAS)

AF:

0.567

AC:

2933

AN:

5170

South Asian (SAS)

AF:

0.697

AC:

3357

AN:

4818

European-Finnish (FIN)

AF:

0.677

AC:

7147

AN:

10564

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.791

AC:

53807

AN:

67990

Other (OTH)

AF:

0.715

AC:

1511

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1529

3058

4588

6117

7646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.761

Hom.:

150715

Bravo

AF:

0.701

Asia WGS

AF:

0.668

AC:

2326

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Dec 02, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Hearing loss, autosomal recessive 94

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Combined oxidative phosphorylation defect type 24

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.3

(source)

DANN

Benign

0.35

PhyloP100

0.066

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over