M-7965-T-C

Variant names:

• chrM-7965-T-C
• rs1556423369
• ENST00000361739.1:c.380T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000361739.1(MT-CO2):​c.380T>C​(p.Phe127Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F127L) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-CO2 ENST00000361739.1 missense
• Scores: Apogee2 Benign 0.086
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 Hepatic-failure-/-COX-deficiency
• Conservation: PhyloP100: 3.45
• Publications: 0 publications found

Genes affected

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]

MT-CO2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

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

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.08594062 < 0.5 .

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361739.1. 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO2	ENST00000361739.1	TSL:6	c.380T>C	p.Phe127Ser	missense	Exon 1 of 1	ENSP00000354876.1

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56428

Alfa AF: 0.000223 Hom.: 0

Mitomap

Disease(s): Hepatic-failure-/-COX-deficiency

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1

Mar 29, 2016

Bodamer Research Lab, Boston Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.086
Hmtvar	Pathogenic	0.65
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.36	T
DEOGEN2	Benign	0.0015	T
LIST_S2	Benign	0.54	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.5
PROVEAN	Benign	2.3	N
Sift	Benign	0.23	T
Sift4G	Uncertain	0.020	D
GERP RS		2.4
Varity_R		0.15

Other links and lift over

dbSNP: rs1556423369; hg19: chrM-7966;