18-9103014-G-A

Variant names:

• chr18-9103014-G-A
• rs142845591
• NM_021074.5:c.54+217G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021074.5(NDUFV2):​c.54+217G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 509,232 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: NDUFV2 NM_021074.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0660
• Publications: 0 publications found

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

ENSG00000265257 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 18-9103014-G-A is Benign according to our data. Variant chr18-9103014-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1219156.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00329 (501/152312) while in subpopulation AFR AF = 0.0115 (478/41578). AF 95% confidence interval is 0.0106. There are 6 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5	c.54+217G>A		intron_variant	Intron 1 of 7	ENST00000318388.11	NP_066552.2
NDUFV2	XR_243808.4	n.99+217G>A		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV2	ENST00000318388.11	c.54+217G>A		intron_variant	Intron 1 of 7	1	NM_021074.5	ENSP00000327268.6

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152194 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000328 AC: 117 AN: 356920 Hom.: 0 Cov.: 4 AF XY: 0.000226 AC XY: 42 AN XY: 186152

African (AFR) AF: 0.0116 AC: 92 AN: 7946

American (AMR) AF: 0.000576 AC: 6 AN: 10414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11554

East Asian (EAS) AF: 0.00 AC: 0 AN: 24360

South Asian (SAS) AF: 0.00 AC: 0 AN: 28880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27880

Middle Eastern (MID) AF: 0.000592 AC: 1 AN: 1688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 222316

Other (OTH) AF: 0.000823 AC: 18 AN: 21882

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152312 Hom.: 6 Cov.: 33 AF XY: 0.00297 AC XY: 221 AN XY: 74482

African (AFR) AF: 0.0115 AC: 478 AN: 41578

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.0000698 Hom.: 0

Bravo AF: 0.00381

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.6
DANN	Benign	0.82
PhyloP100		0.066
PromoterAI		-0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs142845591; hg19: chr18-9103012;