M-12338-T-C

Variant names:

• chrM-12338-T-C
• rs201863060
• ENST00000361567.2:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PVS1 BP6_Moderate BS2

The ENST00000361567.2(MT-ND5):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0033 (AC: 201)
• Consequence: MT-ND5 ENST00000361567.2 start_lost
• Scores: Apogee2 Benign 0.29
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 DEAF1555-increased-penetrance-/-LHON-/-MIDD
• Conservation: PhyloP100: 2.29
• Publications: 10 publications found

Genes affected

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)

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

TRNS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 3 codons. Genomic position: 12343. Lost 0.004 part of the original CDS.
• BP6: Variant M-12338-T-C is Benign according to our data. Variant chrM-12338-T-C is described in ClinVar as Benign. ClinVar VariationId is 29999.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 70

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361567.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND5	ENST00000361567.2	TSL:6	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	ENSP00000354813.2
	MT-ND4	ENST00000361381.2	TSL:6	c.*201T>C		downstream_gene	N/A	ENSP00000354961.2
	MT-TH	ENST00000387441.1	TSL:6	n.*132T>C		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0033 AC: 201

Gnomad homoplasmic AF: 0.0012 AC: 70 AN: 56430

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56430

Alfa AF: 0.000740 Hom.: 12

Mitomap

Disease(s): DEAF1555-increased-penetrance-/-LHON-/-MIDD

Status: Conflicting-reports

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1

May 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Leigh syndrome Benign:1

Oct 17, 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.12338T>C (YP_003024036.1:p.Met1?) variant in MTND5 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.29
Hmtvar	Pathogenic	0.49
BayesDel_addAF	Benign	-0.43	T
PhyloP100		2.3
GERP RS		3.3
Varity_R		0.47
Mutation Taster		=110/90	polymorphism

Other links and lift over

dbSNP: rs201863060; hg19: chrM-12339;