Variant M-12294-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000387456.1(MT-TL2):n.29G>A variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Mitomap GenBank:

Absent

Consequence

MT-TL2
ENST00000387456.1 non_coding_transcript_exon

Scores

Mitotip

Uncertain

Clinical Significance

Uncertain significance reviewed by expert panel U:1

CPEO-/-EXIT+Ophthalmoplegia

Conservation

PhyloP100: 5.30

Variant links:

Genes affected

MT-TL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

MT-TL2 links:

TRNL2 (HGNC:):

TRNL2 links:

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND5 links:

MT-TS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

MT-TS2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNL2	TRNL2.1 use as main transcript	n.29G>A		non_coding_transcript_exon_variant	1/1
TRNS2	TRNS2.1 use as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	Appris
MT-TL2	ENST00000387456.1 linkuse as main transcript	n.29G>A	non_coding_transcript_exon_variant	1/1
MT-ND5	ENST00000361567.2 linkuse as main transcript		upstream_gene_variant		P1
MT-TS2	ENST00000387449.1 linkuse as main transcript		downstream_gene_variant

Frequencies

GnomAD4 exome

Cov.:

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

CPEO-/-EXIT+Ophthalmoplegia

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mitochondrial disease

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Oct 24, 2022

The m.12294G>A variant in MT-TL2 has been reported in two unrelated individuals with primary mitochondrial disease. These two affected individuals had myopathy and ophthalmoplegia. Age of onset ranged from childhood to teens. Muscle biopsies revealed ragged red fibers, COX-deficient fibers, and combined respiratory chain enzyme activity deficiencies. The variant was identified in muscle in both individuals (one with the variant at 59.8% heteroplasmy and the other at 75% heteroplasmy) and was absent in other tissues tested (blood, urine, buccal, primary myoblasts; PS4_supporting, PMIDs: 14581685, 29052516). There are no large families reported in the medical literature to consider for evidence of segregation. The variant was confirmed to have occurred de novo in one of the reported individuals (absent in healthy mother’s muscle; PMID: 29052516, PM6_supporting). In silico predictors do not agree as the computational predictor MitoTIP suggests this variant is pathogenic (71.4 percentile) and HmtVAR predicts it to be likely polymorphic (0.15). This variant is absent in the Genbank dataset, Helix dataset and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (92.9% ± 7.4, n=10) than in COX-positive fibers (48.3% ± 22.19, n=18, p<0.00001; PS3_supporting, PMID: 14581685). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PM2_supporting, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mitotip

Uncertain

Hmtvar

Benign

0.15

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.