M-4604-CA-C

Position:

• chrM-4604-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000361453.3(MT-ND2):​c.142del​(p.Met48Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND2 ENST00000361453.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 Unspecified-suspected-mitochondrial-disorder
• Conservation: PhyloP100: 0.552

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.869 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-4604-CA-C is Pathogenic according to our data. Variant chrM-4604-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692466.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND2	ENST00000361453.3	c.142del	p.Met48Ter	frameshift_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Unspecified-suspected-mitochondrial-disorder

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

The NC_012920.1:m.4611delA (YP_003024027.1:p.Met48Ter) variant in MTND2 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS6, PP4, PP7 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603219523; hg19: chrM-4605;