rs1603223633

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrM-12236-GC-G
• chrM-12236-GC-GCC

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA915952144/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 14)
• Consequence: TRNS2 unassigned_transcript_4813 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
• Publications: 0 publications found

Genes affected

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

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-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]

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

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

TRNH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387449.1. 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-TS2	ENST00000387449.1	TSL:6	n.35delC		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-100delC		upstream_gene	N/A	ENSP00000354813.2	P03915
	MT-ND4	ENST00000361381.2	TSL:6	c.*100delC		downstream_gene	N/A	ENSP00000354961.2	P03905

Frequencies

Mitomap GenBank AF: 0.00020 AC: 14

Mitomap

No disease associated.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	MELAS syndrome (1)
-	1	-	Mitochondrial disease (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	2.2
PhyloP100		-4.2

Other links and lift over

dbSNP: rs1603223633; hg19: chrM-12237;