rs207460003

Variant names:

• chrM-15498-G-A
• rs207460003
• ENST00000361789.2:c.752G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The ENST00000361789.2(MT-CYB):​c.752G>A​(p.Gly251Asp) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G251S) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.00020 (AC: 15)
• Consequence: MT-CYB ENST00000361789.2 missense
• Scores: Apogee2 Pathogenic 0.63
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 DEAF-/-Infantile-histiocytoid-cardiomyopathy
• Conservation: PhyloP100: 3.78
• Publications: 15 publications found

Genes affected

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

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

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Apogee2 supports a deletorius effect, 0.62684804 >= 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 16

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.752G>A	p.Gly251Asp	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CYB	ENST00000361789.2	c.752G>A	p.Gly251Asp	missense_variant	Exon 1 of 1	6		ENSP00000354554.2

Frequencies

Mitomap GenBank AF: 0.00020 AC: 15

Gnomad homoplasmic AF: 0.00028 AC: 16 AN: 56408

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56408

Alfa AF: 0.000445 Hom.: 2

Mitomap

Disease(s): DEAF-/-Infantile-histiocytoid-cardiomyopathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Histiocytoid cardiomyopathy Pathogenic:1

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.15498G>A (YP_003024038.1:p.Gly251Asp) variant in MTCYB gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM10, PP4, PP6, BS1, BP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.63
Hmtvar	Pathogenic	0.69
AlphaMissense	Uncertain	0.45
PhyloP100		3.8

Other links and lift over

dbSNP: rs207460003; hg19: chrM-15499; COSMIC: COSV104420728; COSMIC: COSV104420728;