dbSNP rs141996297: CARS2:c.1317+10C>T (chr13-110645957-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_024537.4(CARS2):c.1317+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 1,610,366 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 63 hom. )

Consequence

CARS2
NM_024537.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.365

Publications

0 publications found

Variant links:

Genes affected

CARS2 (HGNC:25695): (cysteinyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative 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 cysteine to tRNA molecules. A splice-site mutation in this gene has been associated with a novel progressive myoclonic epilepsy disease with similar symptoms to MERRF syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

CARS2 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 27
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Laboratory for Molecular Medicine
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

CARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 13-110645957-G-A is Benign according to our data. Variant chr13-110645957-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024537.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CARS2	NM_024537.4	MANE Select	c.1317+10C>T	intron	N/A	NP_078813.1	Q9HA77
CARS2	NM_001352252.2		c.531+10C>T	intron	N/A	NP_001339181.1
CARS2	NR_147941.1		n.1288+10C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CARS2	ENST00000257347.9	TSL:1 MANE Select	c.1317+10C>T	intron	N/A	ENSP00000257347.4	Q9HA77
CARS2	ENST00000939453.1		c.1461+10C>T	intron	N/A	ENSP00000609512.1
CARS2	ENST00000890914.1		c.1311+10C>T	intron	N/A	ENSP00000560973.1

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

893

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0340

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00767

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00747

AC:

1842

AN:

246726

AF XY:

0.00806

show subpopulations

Gnomad AFR exome

AF:

0.00100

Gnomad AMR exome

AF:

0.00313

Gnomad ASJ exome

AF:

0.0307

Gnomad EAS exome

AF:

0.000500

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00831

Gnomad OTH exome

AF:

0.00820

GnomAD4 exome

AF:

0.00719

AC:

10479

AN:

1458050

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

5453

AN XY:

725350

show subpopulations

African (AFR)

AF:

0.000813

AC:

AN:

33216

American (AMR)

AF:

0.00368

AC:

162

AN:

44006

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

809

AN:

25998

East Asian (EAS)

AF:

0.000203

AC:

AN:

39378

South Asian (SAS)

AF:

0.0117

AC:

1004

AN:

85688

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53364

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00699

AC:

7762

AN:

1110446

Other (OTH)

AF:

0.00860

AC:

518

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

495

990

1484

1979

2474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.00585

AC:

891

AN:

152316

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

425

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41580

American (AMR)

AF:

0.00575

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

118

AN:

3470

East Asian (EAS)

AF:

0.000388

AC:

AN:

5160

South Asian (SAS)

AF:

0.0108

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00767

AC:

522

AN:

68022

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00787

Hom.:

Bravo

AF:

0.00628

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Combined oxidative phosphorylation defect type 27 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.4

(source)

DANN

Benign

0.33

PhyloP100

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over