rs878853104

Variant names:

• chrM-14393-A-G
• rs878853104
• ENST00000361681.2:c.281T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361681.2(MT-ND6):​c.281T>C​(p.Val94Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.00090 (AC: 55)
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Benign 0.064
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 No linked disesase in Mitomap
• Conservation: PhyloP100: 0.451
• Publications: 1 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-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-ND5 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.063702226 < 0.5 .
• BP6: Variant M-14393-A-G is Benign according to our data. Variant chrM-14393-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 235743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 59

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.281T>C	p.Val94Ala	missense_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.*245A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND6	ENST00000361681.2	c.281T>C	p.Val94Ala	missense_variant	Exon 1 of 1	6		ENSP00000354665.2
MT-ND5	ENST00000361567.2	c.*245A>G		downstream_gene_variant		6		ENSP00000354813.2

Frequencies

Mitomap GenBank AF: 0.00090 AC: 55

Gnomad homoplasmic AF: 0.0010 AC: 59 AN: 56430

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56430

Mitomap

No disease associated.

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.14393A>G (YP_003024037.1:p.Val94Ala) variant in MTND6 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2, BP4 -

not provided Benign:1

Aug 12, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.064
Hmtvar	Benign	0.13
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.50	T
DEOGEN2	Benign	0.36	T
LIST_S2	Benign	0.52	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.45
PROVEAN	Benign	-1.9	N
Sift	Benign	0.049	D
Sift4G	Benign	0.12	T
GERP RS		-0.68
Varity_R		0.23
Mutation Taster		=93/7	polymorphism

Other links and lift over

dbSNP: rs878853104; hg19: chrM-14394;