rs1556423442

Variant names:

• chrM-8393-C-T
• rs1556423442
• ENST00000361851.1:c.28C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The ENST00000361851.1(MT-ATP8):​c.28C>T​(p.Pro10Ser) 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10L) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0051 (AC: 311)
• Consequence: MT-ATP8 ENST00000361851.1 missense
• Scores: Apogee2 Benign 0.048
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1 Reversible-brain-pseudoatrophy
• Conservation: PhyloP100: -0.220
• Publications: 0 publications found

Genes affected

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

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]

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

TRNK Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• maternally-inherited cardiomyopathy and hearing loss

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.04838793 < 0.5 .
• BP6: Variant M-8393-C-T is Benign according to our data. Variant chrM-8393-C-T is described in ClinVar as Benign. ClinVar VariationId is 9638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: High frequency in mitomap database: 0.0050999997
• BS2: High AC in GnomadMitoHomoplasmic at 274

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8	unassigned_transcript_4804	c.28C>T	p.Pro10Ser	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.-134C>T		upstream_gene_variant
COX2	unassigned_transcript_4802	c.*124C>T		downstream_gene_variant
TRNK	unassigned_transcript_4803	c.*29C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP8	ENST00000361851.1	c.28C>T	p.Pro10Ser	missense_variant	Exon 1 of 1	6		ENSP00000355265.1
MT-ATP6	ENST00000361899.2	c.-134C>T		upstream_gene_variant		6		ENSP00000354632.2
MT-CO2	ENST00000361739.1	c.*124C>T		downstream_gene_variant		6		ENSP00000354876.1
MT-TK	ENST00000387421.1	n.*29C>T		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0051 AC: 311

Gnomad homoplasmic AF: 0.0049 AC: 274 AN: 56434

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56434

Alfa AF: 0.00779 Hom.: 35

Mitomap

Disease(s): Reversible-brain-pseudoatrophy

Status: Reported

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8393C>T (YP_003024030.1:p.Pro10Ser) variant in MTATP8 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2

Brain pseudoatrophy, reversible, valproate-induced, susceptibility to Other:1

Nov 14, 2006

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.048
Hmtvar	Pathogenic	0.67
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.42	T
DEOGEN2	Benign	0.041	T
LIST_S2	Benign	0.65	T
PhyloP100		-0.22
PROVEAN	Benign	-1.3	N
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
GERP RS		-2.9
Varity_R		0.066
Mutation Taster		=99/1	polymorphism

Other links and lift over

dbSNP: rs1556423442; hg19: chrM-8394;