M-7649-A-G

Position:

• chrM-7649-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4 BP6_Moderate BS2

The ENST00000361739.1(MT-CO2):​c.64A>G​(p.Thr22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T22I) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: MT-CO2 ENST00000361739.1 missense
• Scores: Apogee2 Benign 0.030
• Clinical Significance: Likely benign criteria provided, single submitter B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -0.372

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 -5 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.030289028 < 0.5 .
• BP6: Variant M-7649-A-G is Benign according to our data. Variant chrM-7649-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 692753.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 10

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX2	COX2.1	c.64A>G	p.Thr22Ala	missense_variant	1/1		YP_003024029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-CO2	ENST00000361739.1	c.64A>G	p.Thr22Ala	missense_variant	1/1			ENSP00000354876	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: 0.00018 AC: 10 AN: 56429

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56429

Mitomap

No disease associated.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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.7649A>G (YP_003024029.1:p.Thr22Ala) 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, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.030
Hmtvar	Benign	0.12
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.44	T
DEOGEN2	Benign	0.0049	T
LIST_S2	Benign	0.012	T
MutationAssessor	Benign	-0.83	N
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.010	N
Sift	Benign	0.20	T
Sift4G	Benign	0.097	T
GERP RS		-7.5
Varity_R		0.080

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603221060; hg19: chrM-7650;