rs267606889

Positions:

• chrM-4681-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000361453.3(MT-ND2):​c.212T>C​(p.Leu71Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L71I) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-ND2 ENST00000361453.3 missense
• Scores: Apogee2 Pathogenic 0.73
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1 Leigh-Syndrome
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP3: Apogee2 supports a deletorius effect, 0.7331313 >= 0.5 .
• PP5: Variant M-4681-T-C is Pathogenic according to our data. Variant chrM-4681-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9721.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.212T>C	p.Leu71Pro	missense_variant	1/1			ENSP00000355046	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 1

Mitomap

Leigh-Syndrome

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Leigh syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.73
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.000084	T
DEOGEN2	Benign	0.30	T
LIST_S2	Benign	0.58	T
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.5e-8	A
PROVEAN	Uncertain	-4.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.3
Varity_R		0.93

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606889; hg19: chrM-4682;