M-5178-C-A

Variant names:

• chrM-5178-C-A
• rs28357984
• ENST00000361453.3:c.709C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The ENST00000361453.3(MT-ND2):​c.709C>A​(p.Leu237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.045 (AC: 2752)
• Consequence: MT-ND2 ENST00000361453.3 missense
• Scores: Apogee2 Benign 0.031
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 Longevity-/-Extraversion-/-diabetes-/-AMS-protection-/-blood-iron-metabolism-/-correlation-with-myocardial-infarction-/-atherosclerosis
• Conservation: PhyloP100: -4.27
• Publications: 39 publications found

Genes affected

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) 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; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

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

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.03096441 < 0.5 .
• BP6: Variant M-5178-C-A is Benign according to our data. Variant chrM-5178-C-A is described in ClinVar as [Benign]. Clinvar id is 692551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: High frequency in mitomap database: 0.045

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND2	unassigned_transcript_4793	c.709C>A	p.Leu237Met	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.709C>A	p.Leu237Met	missense_variant	Exon 1 of 1	6		ENSP00000355046.4

Frequencies

Mitomap GenBank AF: 0.045 AC: 2752

Gnomad homoplasmic AF: 0.011 AC: 603 AN: 56426

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56426

Alfa AF: 0.00636 Hom.: 28

Mitomap

Disease(s): Longevity-/-Extraversion-/-diabetes-/-AMS-protection-/-blood-iron-metabolism-/-correlation-with-myocardial-infarction-/-atherosclerosis

Status: Reported

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.5178C>A (YP_003024027.1:p.Leu237Met) variant in MTND2 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.031
Hmtvar	Pathogenic	0.63
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.23	T
DEOGEN2	Benign	0.011	T
LIST_S2	Benign	0.72	T
MutationAssessor	Benign	1.1	L
PhyloP100		-4.3
PROVEAN	Benign	-0.39	N
GERP RS		-10
Varity_R		0.41
Mutation Taster		=97/3	polymorphism

Other links and lift over

dbSNP: rs28357984; hg19: chrM-5179;