Genetic Variant NDUFV2:p.Ala16Pro (chr18-9102789-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021074.5(NDUFV2):c.46G>C(p.Ala16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A16T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NDUFV2
NM_021074.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

0 publications found

Variant links:

Genes affected

NDUFV2 (HGNC:7717): (NADH:ubiquinone oxidoreductase core subunit V2) The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes the 24 kDa subunit of complex I, and is involved in electron transfer. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy. A non-transcribed pseudogene of this locus is found on chromosome 19. [provided by RefSeq, Oct 2009]

NDUFV2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency, nuclear type 7
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NDUFV2 links:

ENSG00000265257 (HGNC:):

ENSG00000265257 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2405999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5 link	c.46G>C	p.Ala16Pro	missense_variant	Exon 1 of 8	ENST00000318388.11	NP_066552.2	P19404
NDUFV2	XR_243808.4 link	n.91G>C		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV2	ENST00000318388.11 link	c.46G>C	p.Ala16Pro	missense_variant	Exon 1 of 8	1	NM_021074.5	ENSP00000327268.6		P19404

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000565

AC:

AN:

177002

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32288

American (AMR)

AF:

0.00

AC:

AN:

38934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25338

East Asian (EAS)

AF:

0.00

AC:

AN:

37536

South Asian (SAS)

AF:

0.00

AC:

AN:

81004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093448

Other (OTH)

AF:

0.00

AC:

AN:

58744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000364

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.00044

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.63

T;.

M_CAP

Benign

0.037

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.49

N;.

PhyloP100

1.2

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.99

N;.

REVEL

Benign

0.23

Sift

Benign

0.063

T;.

Sift4G

Benign

0.25

T;.

Polyphen

0.21

B;.

Vest4

0.64

MutPred

0.41

Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);

MVP

0.15

MPC

0.055

ClinPred

0.10

GERP RS

-0.074

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.22

gMVP

0.49

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over