rs28461189

chrM-6489-C-AchrM-6489-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PS1_Moderate BP4 BP6_Moderate BS2

The ENST00000361624.2(MT-CO1):c.586C>A(p.Leu196Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Mitomap GenBank: 𝑓 0.0015 (AC: 90)
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Benign 0.33
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 CO1-deficiency-with-epilepsia-partialis-continua
• Conservation: PhyloP100: 0.0840

Genes affected

COX1 (HGNC:):

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PS1: Transcript ENST00000361624.2 (MT-CO1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Apogee2 supports a benign effect, 0.32893616 < 0.5 .
• BP6: Variant M-6489-C-A is Benign according to our data. Variant chrM-6489-C-A is described in ClinVar as [Benign]. Clinvar id is 9670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 185

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX1	COX1.1	c.586C>A	p.Leu196Ile	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO1	ENST00000361624.2	c.586C>A	p.Leu196Ile	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: 0.0015 AC: 90

Gnomad homoplasmic AF: 0.0033 AC: 185 AN: 56432

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56432

Alfa AF: 0.00289 Hom.: 13

Mitomap

CO1-deficiency-with-epilepsia-partialis-continua

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cytochrome c oxidase I deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

Leigh syndrome Benign:1

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.6489C>A (YP_003024028.1:p.Leu196Ile) variant in MTCO1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.33
Hmtvar	Pathogenic	0.73
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.091	D
DEOGEN2	Benign	0.044	T
LIST_S2	Benign	0.69	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.0048	A
PROVEAN	Benign	-1.5	N
Sift4G	Uncertain	0.020	D
GERP RS		1.1
Varity_R		0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28461189; hg19: chrM-6490;