Variant 5-140645661-TC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The ENST00000252102.9(NDUFA2):c.225del(p.Asn76MetfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T75T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NDUFA2
ENST00000252102.9 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 0.209

Variant links:

Genes affected

NDUFA2 (HGNC:7685): (NADH:ubiquinone oxidoreductase subunit A2) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

NDUFA2 links:

TMCO6 (HGNC:):

TMCO6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-140645661-TC-T is Pathogenic according to our data. Variant chr5-140645661-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214712.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA2	NM_002488.5 linkuse as main transcript	c.225del	p.Asn76MetfsTer4	frameshift_variant	3/3	ENST00000252102.9	NP_002479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA2	ENST00000252102.9 linkuse as main transcript	c.225del	p.Asn76MetfsTer4	frameshift_variant	3/3	1	NM_002488.5	ENSP00000252102	P1	O43678-1
NDUFA2	ENST00000512088.1 linkuse as main transcript	c.*41del		3_prime_UTR_variant	3/3	2		ENSP00000427220		O43678-2
NDUFA2	ENST00000502960.1 linkuse as main transcript	n.533del		non_coding_transcript_exon_variant	2/2	2
NDUFA2	ENST00000510680.1 linkuse as main transcript	n.59+1594del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in abnormal protein length as the last 24 amino acids are replaced with 3 different amino acids; This variant is associated with the following publications: (PMID: 27159321, 32154054, 28857146, 33233646, 32304865) -

Cystic Leukoencephalopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

MyeliNeuroGene Lab, McGill University Health Center Research Institute

This is the first report of autosomal recessive mutations in NDUFA2 associated with cystic leukoencephalopathy. -

Mitochondrial complex 1 deficiency, nuclear type 13

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over