chrM-12308-A-G

Position:

• chrM-12308-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The m.12308A>G variant in MT-TL2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant is seen in 12.5% of individuals in the GenBank dataset (BA1) including in haplogroups K (99.5% of individuals) and U (98.9% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 15% including in haplogroups K (99.9% of individuals) and U (99.7% of individuals). If an affected individual is not a member one of these haplogroups, further evaluation of the variant in that particular individual should be considered. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA337099441/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.13 (AC: 7883)
• Consequence: MT-TL2 ENST00000387456.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 12
• Clinical Significance: Benign reviewed by expert panel B:2 CPEO-/-Stroke-/-CM-/-Breast-&-Renal-&-Prostate-Cancer-Risk-/-Altered-brain-pH-/sCJD
• Conservation: PhyloP100: 0.785

Genes affected

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

TRNL2 (HGNC:):

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

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNL2	TRNL2.1	n.43A>G		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.43A>G		non_coding_transcript_exon_variant	1/1
MT-ND5	ENST00000361567.2			upstream_gene_variant				P1
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.

Mitomap GenBank AF: 0.13 AC: 7883

Gnomad homoplasmic AF: 0.16 AC: 8754 AN: 56336

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56336

Alfa AF: 0.217 Hom.: 8634

Mitomap

CPEO-/-Stroke-/-CM-/-Breast-&-Renal-&-Prostate-Cancer-Risk-/-Altered-brain-pH-/sCJD

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Benign:1

Benign, reviewed by expert panel

curation

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

Jan 10, 2022

The m.12308A>G variant in MT-TL2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in 12.5% of individuals in the GenBank dataset (BA1) including in haplogroups K (99.5% of individuals) and U (98.9% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 15% including in haplogroups K (99.9% of individuals) and U (99.7% of individuals). If an affected individual is not a member one of these haplogroups, further evaluation of the variant in that particular individual should be considered. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1. -

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

Benign, 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.12308A>G variant in MT-TL2 gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BA1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2853498; hg19: chrM-12309;