chrM-12236-GC-G

Position:

• chrM-12236-GC-G

Variant summary

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

The ENST00000387449.1(MT-TS2):​n.35del variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 14)
• Consequence: MT-TS2 ENST00000387449.1 non_coding_transcript_exon
• 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

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

TRNS2 (HGNC:):

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

MT-TH (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: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNS2	TRNS2.1	n.35del		non_coding_transcript_exon_variant	1/1
TRNL2	TRNL2.1			upstream_gene_variant
TRNH	TRNH.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TS2	ENST00000387449.1	n.35del		non_coding_transcript_exon_variant	1/1
MT-TL2	ENST00000387456.1			upstream_gene_variant
MT-TH	ENST00000387441.1			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: 0.00020 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

Uncertain significance, reviewed by expert panel

curation

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

Aug 22, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 07, 2019

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. -

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.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;