M-7637-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BP6_Strong

The ENST00000361739.1(MT-CO2):c.52G>A(p.Glu18Lys) 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 Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: MT-CO2 ENST00000361739.1 missense
• Scores: Apogee2 Pathogenic 0.55
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 PD-risk-factor
• Conservation: PhyloP100: 9.55

Genes affected

COX2 (HGNC:):

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP3: Apogee2 supports a deletorius effect, 0.5530385 >= 0.5 .
• BP6: Variant M-7637-G-A is Benign according to our data. Variant chrM-7637-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 439912.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX2	COX2.1	c.52G>A	p.Glu18Lys	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO2	ENST00000361739.1	c.52G>A	p.Glu18Lys	missense_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 GenBank AF: 0.0 AC: 2

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56427

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56427

Alfa AF: 0.000334 Hom.: 1

Mitomap

PD-risk-factor

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 11, 2017

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jun 26, 2023

The m.7637G>A (p.E18K) variant in MT-CO2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual with Parkinson disease with haplogroup Uk1 (PMID: 19076426). There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 2/59,389 (0.003%). The frequency in gnomAD v3.1.2 is 6/56,427 (0.011%). This includes three homoplasmic occurrences (two European, one African/African American, haplogroups T, J, L2) and three heteroplasmic occurrences (two European, one African/African American; haplogroups K, L3, U; one with 10-20% heteroplasmy, one with 30-40% heteroplasmy, one with 60-70% heteroplasmy; two individuals in 70-75-year-old range with details not provided on other individuals). The frequency in the Helix dataset is 16/195,983 (0.008%) including 12 homoplasmic occurrences (haplogroups T=6, H=3, A=1, C=1, L2=1) and four heteroplasmic occurrences (haplogroup J=1, K=1, L3=1, T=1). Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). There are no cybrids, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.91 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP3. -

Leigh syndrome Benign:1

Likely benign, 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.7637G>A (YP_003024029.1:p.Glu18Lys) variant in MTCO2 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS4, BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.55
Hmtvar	Pathogenic	0.88
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.097	T
DEOGEN2	Benign	0.10	T
LIST_S2	Benign	0.82	T
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	0.99	D
PROVEAN	Uncertain	-3.9	D
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
GERP RS		5.2
Varity_R		0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556423314; hg19: chrM-7638; COSMIC: COSV104668817; COSMIC: COSV104668817;