rs28461189

Variant names:

• chrM-6489-C-A
• rs28461189
• ENST00000361624.2:c.586C>A

Your query was ambiguous. Multiple possible variants found:

• chrM-6489-C-A
• chrM-6489-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong 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 Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.0015 (AC: 90)
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Benign 0.33
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2 CO1-deficiency-with-epilepsia-partialis-continua
• Conservation: PhyloP100: 0.0840
• Publications: 16 publications found

Genes affected

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]

MT-CO1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial non-syndromic sensorineural hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• 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 [Likely_benign]. Clinvar id is 9670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 185

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX1	unassigned_transcript_4799	c.586C>A	p.Leu196Ile	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.586C>A	p.Leu196Ile	missense_variant	Exon 1 of 1	6		ENSP00000354499.2

Frequencies

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: 0.00327 Hom.: 53

Mitomap

Disease(s): CO1-deficiency-with-epilepsia-partialis-continua

Status: Reported

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cytochrome c oxidase I deficiency Pathogenic:1

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.084
PROVEAN	Benign	-1.5	N
Sift4G	Uncertain	0.020	D
GERP RS		1.1
Varity_R		0.70
Mutation Taster		=55/45	polymorphism

Other links and lift over

dbSNP: rs28461189; hg19: chrM-6490;