chrM-5244-G-A

Position:

• chrM-5244-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ND2 missense
• Scores: Apogee2 Pathogenic 0.95
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 LHON
• Conservation: PhyloP100: 5.45

Genes affected

ND2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ND2	unassigned_transcript_4794	c.775G>A	p.Gly259Ser	missense_variant	1/1

Ensembl

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

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

LHON

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Oct 09, 2023

The m.5244G>A (p.G259S) variant in MT-ND2 has been reported in one family (PMID: 1634041) with Leber Hereditary Optic Neuropathy (LHON), however individuals in this family also harbored other mitochondrial DNA variants also associated with LHON, making the association of this variant to the primary mitochondrial disease features in these individuals unclear. Furthermore, to our knowledge, nuclear genetic testing was not performed. There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (77 percentile, PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.95
Hmtvar	Pathogenic	0.83
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
DEOGEN2	Benign	0.18	T
LIST_S2	Uncertain	0.97	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	0.0000014	A
PROVEAN	Pathogenic	-5.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476115; hg19: chrM-5245;