rs200336777

Positions:

• chrM-15812-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PS1_Moderate BP4 BP6_Moderate BS1 BS2

The ENST00000361789.2(MT-CYB):​c.1066G>A​(p.Val356Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V356A) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0084 (AC: 513)
• Consequence: MT-CYB ENST00000361789.2 missense
• Scores: Apogee2 Benign 0.098
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 LHON
• Conservation: PhyloP100: -0.327

Genes affected

CYTB (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PS1: Transcript ENST00000361789.2 (MT-CYB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Apogee2 supports a benign effect, 0.09807686 < 0.5 .
• BP6: Variant M-15812-G-A is Benign according to our data. Variant chrM-15812-G-A is described in ClinVar as [Benign]. Clinvar id is 9675.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: High frequency in mitomap database: 0.0084
• BS2: High AC in GnomadMitoHomoplasmic at 656

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYTB	CYTB.1	c.1066G>A	p.Val356Met	missense_variant	1/1		YP_003024038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-CYB	ENST00000361789.2	c.1066G>A	p.Val356Met	missense_variant	1/1			ENSP00000354554	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0084 AC: 513

Gnomad homoplasmic AF: 0.012 AC: 656 AN: 56424

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56424

Alfa AF: 0.00613 Hom.: 41

Mitomap

LHON

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1992

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

The NC_012920.1:m.15812G>A (YP_003024038.1:p.Val356Met) variant in MTCYB gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.098
Hmtvar	Benign	0.14
AlphaMissense	Benign	0.095

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200336777; hg19: chrM-15813;