chrM-12278-T-C

Position:

• chrM-12278-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000387456.1(MT-TL2):​n.13T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TL2 ENST00000387456.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 MODY-diabetes-mellitus
• Conservation: PhyloP100: 2.93

Genes affected

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

TRNL2 (HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-12278-T-C is Pathogenic according to our data. Variant chrM-12278-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 690182.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNL2	TRNL2.1	n.13T>C		non_coding_transcript_exon_variant	1/1
TRNS2	TRNS2.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TL2	ENST00000387456.1	n.13T>C		non_coding_transcript_exon_variant	1/1
MT-TS2	ENST00000387449.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56425

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56425

Mitomap

MODY-diabetes-mellitus

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Diabetes-deafness syndrome maternally transmitted Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Department of Clinical Genetics, Medical University of Lodz

Feb 19, 2024

- -

Mitochondrial disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

-

- The T at this position has high conservation (MITOMASTER). - In silico predictions for this variant are consistently pathogenic (MitoTIP, PON-tRNA). - This variant is present in the MITOMAP and gnomAD population databases at frequencies of 0.002% and 0.004%, respectively. Additional information: - This variant is heteroplasmic (83.8%). - This gene encodes a mitochondrial tRNA (Leu (CUN)). - This variant is predicted to result in a nucleotide change from T to C . - This variant is located in the D-stem of the tRNA and disrupts a Watson-Crick base pairing. - The pairing nucleotide at this position in the stem (m.12286A) has high conservation (MITOMASTER). - This variant has been previously reported as likely pathogenic in two individuals with adult-onset chronic progressive external ophthalmoplegia (CPEO). It was 40.7% heteroplasmic in the muscle sample of one of the individuals. It was 18.3% heteroplasmic in the muscle sample of the other individual, who also had a pathogenic POLG variant. (PMID: 31521625) This variant has also been previously reported as uncertain significance in ClinVar . - This variant is likely maternally inherited. It has been detected in the maternal blood sample at a low heteroplasmy level (~1.9%). -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Jul 12, 2019

The NC_012920.1:m.12278T>C variant in MT-TL2 gene is interpreted to be a Unknown Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PM7, PP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Benign	0.15

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603223646; hg19: chrM-12279;