Variant rs757982865 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_002488.5(NDUFA2):c.134A>C(p.Lys45Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,452,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NDUFA2
NM_002488.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.04

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:

IK (HGNC:5958): (IK cytokine) The protein encoded by this gene was identified by its RED repeat, a stretch of repeated arginine, glutamic acid and aspartic acid residues. The protein localizes to discrete dots within the nucleus, excluding the nucleolus. Its function is unknown. This gene maps to chromosome 5; however, a pseudogene may exist on chromosome 2. [provided by RefSeq, Jul 2008]

IK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 5-140647330-T-G is Pathogenic according to our data. Variant chr5-140647330-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 214711.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NDUFA2	NM_002488.5 linkuse as main transcript	c.134A>C	p.Lys45Thr	missense_variant	2/3	ENST00000252102.9	NP_002479.1
NDUFA2	NM_001185012.2 linkuse as main transcript	c.134A>C	p.Lys45Thr	missense_variant	2/3		NP_001171941.1
TMCO6	XM_047417354.1 linkuse as main transcript	c.*513T>G		3_prime_UTR_variant	11/11		XP_047273310.1
NDUFA2	NR_033697.2 linkuse as main transcript	n.301A>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA2	ENST00000252102.9 linkuse as main transcript	c.134A>C	p.Lys45Thr	missense_variant	2/3	1	NM_002488.5	ENSP00000252102	P1	O43678-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247510

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000335

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721320

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:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cystic Leukoencephalopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;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 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

-0.24

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.93

MutPred

0.79

Loss of methylation at K45 (P = 0.0129);Loss of methylation at K45 (P = 0.0129);

MVP

0.40

MPC

1.2

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.97

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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