rs1556423369

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 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX2	unassigned_transcript_4802	c.380T>C	p.Phe127Ser	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO2	ENST00000361739.1	c.380T>C	p.Phe127Ser	missense_variant	Exon 1 of 1	6		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

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Computational scores

Source: dbNSFP v4.3

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;