chrM-8296-A-G

Variant names:

• chrM-8296-A-G
• rs118192102
• unassigned_transcript_4803:c.2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The m.8296A>G variant in MT-TK has been reported in 18 unrelated individuals with primary mitochondrial disease with varying phenotypes (diabetes, hypertrophic cardiomyopathy, optic atrophy, sensorineural hearing loss, and generalized epilepsy; 10 subjects reported in PMIDs: 9802769, 9571188, 10525672; additional subjects reported in PMIDs: 10737988, 12504210, 18651333, 20143911, 37573175), however analyses for other genetic etiologies were limited in these affected individuals precluding their inclusion in this curation. The variant was present in some affected individuals at homoplasmy and in others at heteroplasmy. In at least one family, the variant was present at homoplasmy in the proband and in his healthy mother and sister (PMID:18651333). There are no reported de novo occurrences to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.061%, 38/61,883; gnomAD v3.1.2: 0.044%, 25/56,432 homoplasmic occurrences, one heteroplasmic occurrence; Helix: 0.048%, 94/195,893 homoplasmic occurrences). The computational predictor MitoTIP suggests this variant is pathogenic (72.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Single fiber testing showed similar levels of the variant in COX-negative ragged red fibers and normal fibers (PMID:9932960), and cybrid studies showed no significant differences from wild type (PMID:11857739). 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 February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120557/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00060 (AC: 38)
• Consequence: TRNK unassigned_transcript_4803 missense
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 B:1 O:1 DMDF-/-MERRF-/-HCM-/-epilepsy-/-hearing-loss
• Conservation: PhyloP100: 1.81
• Publications: 4 publications found

Genes affected

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387421.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TK	ENST00000387421.1	TSL:6	n.2A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ATP6	ENST00000361899.2	TSL:6	c.-231A>G		upstream_gene	N/A	ENSP00000354632.2	P00846
	MT-ATP8	ENST00000361851.1	TSL:6	c.-70A>G		upstream_gene	N/A	ENSP00000355265.1	P03928

Frequencies

Mitomap GenBank AF: 0.00060 AC: 38

Gnomad homoplasmic AF: 0.00044 AC: 25 AN: 56432

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56432

Alfa AF: 0.000212 Hom.: 1

Mitomap

Disease(s): DMDF-/-MERRF-/-HCM-/-epilepsy-/-hearing-loss

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Diabetes-deafness syndrome maternally transmitted (1)
-	-	1	MELAS syndrome (2)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.85
PhyloP100		1.8

Other links and lift over

dbSNP: rs118192102; hg19: chrM-8297;