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 Benign/Likely_benign. ClinVar VariationId is 9670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 185

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361624.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO1	ENST00000361624.2	TSL:6	c.586C>A	p.Leu196Ile	missense	Exon 1 of 1	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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Cytochrome c oxidase I deficiency (1)
-	-	1	Leigh syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;