18-9102771-C-T

Variant names:

• chr18-9102771-C-T
• rs760685057
• NM_021074.5:c.28C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021074.5(NDUFV2):​c.28C>T​(p.Arg10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,431,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: NDUFV2 NM_021074.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.303

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]

ENSG00000265257 (HGNC:):

ACMG classification

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=0.114314914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5	c.28C>T	p.Arg10Trp	missense_variant	Exon 1 of 8	ENST00000318388.11	NP_066552.2
NDUFV2	XR_243808.4	n.73C>T		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	c.28C>T	p.Arg10Trp	missense_variant	Exon 1 of 8	1	NM_021074.5	ENSP00000327268.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1431352 Hom.: 0 Cov.: 31 AF XY: 0.00000423 AC XY: 3 AN XY: 709512

African (AFR) AF: 0.0000308 AC: 1 AN: 32476

American (AMR) AF: 0.00 AC: 0 AN: 40616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 38086

South Asian (SAS) AF: 0.0000244 AC: 2 AN: 82118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4224

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099184

Other (OTH) AF: 0.00 AC: 0 AN: 59086

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.83	T;.
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		-0.30
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.31	N;.
REVEL	Benign	0.067
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.028	D;.
Polyphen		0.0	B;.
Vest4		0.50
MutPred		0.44		Loss of methylation at R10 (P = 0.0037);Loss of methylation at R10 (P = 0.0037);
MVP		0.17
MPC		0.042
ClinPred		0.092	T
GERP RS		-6.6
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.5
Varity_R		0.077
gMVP		0.60
Mutation Taster		=95/5	polymorphism

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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Other links and lift over

dbSNP: rs760685057; hg19: chr18-9102769; COSMIC: COSV59188428; COSMIC: COSV59188428;