dbSNP rs1398511016: CARS2:p.Pro8Pro (chr13-110706070-T-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_024537.4(CARS2):c.24A>T(p.Pro8Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,184,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

CARS2
NM_024537.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.59

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, Laboratory for Molecular Medicine, G2P
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: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 13-110706070-T-A is Benign according to our data. Variant chr13-110706070-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 475627.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.59 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS2	NM_024537.4 link	c.24A>T	p.Pro8Pro	synonymous_variant	Exon 1 of 15	ENST00000257347.9	NP_078813.1	Q9HA77B7Z7E6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS2	ENST00000257347.9 link	c.24A>T	p.Pro8Pro	synonymous_variant	Exon 1 of 15	1	NM_024537.4	ENSP00000257347.4		Q9HA77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000253

AC:

AN:

1184964

Hom.:

Cov.:

AF XY:

0.00000345

AC XY:

AN XY:

579242

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000418

AC:

AN:

23898

American (AMR)

AF:

0.00

AC:

AN:

15510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17308

East Asian (EAS)

AF:

0.0000394

AC:

AN:

25378

South Asian (SAS)

AF:

0.00

AC:

AN:

48694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4422

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

975334

Other (OTH)

AF:

0.0000211

AC:

AN:

47414

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 27

Benign:1

Apr 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.76

CADD

Benign

5.6

(source)

DANN

Benign

0.66

PhyloP100

-2.6

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over