M-12236-GC-G

Variant names:

• chrM-12236-GC-G
• rs1603223633
• unassigned_transcript_4813:c.35delC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP6_Strong

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 14)
• Consequence: TRNS2 frameshift
• Scores: Mitotip Benign 2.2
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -4.19

Genes affected

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

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]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) 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; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP6: Variant M-12236-GC-G is Benign according to our data. Variant chrM-12236-GC-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 690169.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNS2	unassigned_transcript_4813	c.35delC	p.Pro12fs	frameshift_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-100delC		upstream_gene_variant
TRNL2	unassigned_transcript_4814	c.-29delC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.00020 AC: 14

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Aug 22, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.12241del variant in MT-TS2 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 16/61,168 (0.026%). The frequency in the Helix dataset is 81/195,983 (0.041%) homoplasmic occurrences in addition to 22 heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 53/56,425 (0.094%) and these occurrences are homoplasmic in individuals from various backgrounds. In all three population databases, this variant is seen across individuals from different haplogroups. MitoTIP suggests this variant is benign (37th percentile; BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. -

See cases Uncertain:1

Nov 07, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state. -

MELAS syndrome Benign:1

Jul 12, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.12241delC variant in MT-TS2 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: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	2.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603223633; hg19: chrM-12237;