rs869025186

Variant names:

• chrM-14498-T-C
• rs869025186
• ENST00000361681.2:c.176A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000361681.2(MT-ND6):​c.176A>G​(p.Tyr59Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.96
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1 LHON
• Conservation: PhyloP100: 3.10
• Publications: 11 publications found

Genes affected

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in ENST00000361681.2
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.96350706 >= 0.5 .

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361681.2. 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-ND6	ENST00000361681.2	TSL:6	c.176A>G	p.Tyr59Cys	missense	Exon 1 of 1	ENSP00000354665.2	P03923
	MT-CYB	ENST00000361789.2	TSL:6	c.-249T>C		upstream_gene	N/A	ENSP00000354554.2	P00156
	MT-TE	ENST00000387459.1	TSL:6	n.*176A>G		downstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): LHON

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)
-	-	-	Leber optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.96
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.061	T
DEOGEN2	Pathogenic	0.85	D
LIST_S2	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		3.1
PROVEAN	Pathogenic	-8.8	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.0
Varity_R		0.92
Mutation Taster		=14/86	disease causing

Other links and lift over

dbSNP: rs869025186; hg19: chrM-14499;