2-197705414-A-G

Variant names:

• chr2-197705414-A-G
• rs2089464842
• NM_138395.4:c.9A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_138395.4(MARS2):​c.9A>G​(p.Arg3Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,888 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MARS2 NM_138395.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84
• Publications: 0 publications found

Genes affected

MARS2 (HGNC:25133): (methionyl-tRNA synthetase 2, mitochondrial) This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3). [provided by RefSeq, Apr 2014]

MARS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• spastic ataxia 3

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• combined oxidative phosphorylation defect type 25

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000222017 (HGNC:):

ACMG classification

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=-0.79).
• BP6: Variant 2-197705414-A-G is Benign according to our data. Variant chr2-197705414-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1964942.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138395.4. 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
	MARS2	NM_138395.4	MANE Select	c.9A>G	p.Arg3Arg	synonymous	Exon 1 of 1	NP_612404.1	Q96GW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARS2	ENST00000282276.8	TSL:6 MANE Select	c.9A>G	p.Arg3Arg	synonymous	Exon 1 of 1	ENSP00000282276.6	Q96GW9
	ENSG00000222017	ENST00000409845.1	TSL:1	n.166+6550A>G		intron	N/A
	ENSG00000222017	ENST00000721462.1		n.213+64913A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724600

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4782

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110298

Other (OTH) AF: 0.0000166 AC: 1 AN: 60152

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.37
DANN	Benign	0.62
PhyloP100		-1.8
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs2089464842; hg19: chr2-198570138;