rs1556424448

Variant names:

• chrM-14477-A-G
• rs1556424448
• ENST00000361681.2:c.197T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000361681.2(MT-ND6):​c.197T>C​(p.Val66Ala) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V66V) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Pathogenic 0.76
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 5.72
• Publications: 0 publications found

Genes affected

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in ENST00000361681.2
• PM2: Very low frequency in mitomap database: 0.0
• PP3: Apogee2 supports a deletorius effect, 0.75750566 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.197T>C	p.Val66Ala	missense_variant	Exon 1 of 1
TRNE	unassigned_transcript_4817	c.*197T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND6	ENST00000361681.2	c.197T>C	p.Val66Ala	missense_variant	Exon 1 of 1	6		ENSP00000354665.2
MT-TE	ENST00000387459.1	n.*197T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 2

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Headache;C0030554:Paresthesia;C0037763:Muscle spasm;C0042571:Vertigo;C0235095:Constriction of peripheral visual field;C0338656:Cognitive impairment;C4021085:Abnormal brain morphology Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.76
Hmtvar	Pathogenic	0.80
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.027	T
DEOGEN2	Pathogenic	0.85	D
LIST_S2	Benign	0.74	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		5.7
PROVEAN	Uncertain	-4.0	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.0
Varity_R		0.84
Mutation Taster		=68/32	polymorphism

Other links and lift over

dbSNP: rs1556424448; hg19: chrM-14478;