18-9103048-GATAT-GATATAT

Variant names:

• chr18-9103048-G-GAT
• rs148124234
• NM_021074.5:c.54+264_54+265dupAT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_021074.5(NDUFV2):​c.54+264_54+265dupAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 472,302 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: NDUFV2 NM_021074.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.747
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000971 (147/151358) while in subpopulation AFR AF = 0.00285 (118/41354). AF 95% confidence interval is 0.00244. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5	c.54+264_54+265dupAT		intron_variant	Intron 1 of 7	ENST00000318388.11	NP_066552.2
NDUFV2	XR_243808.4	n.99+264_99+265dupAT		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV2	ENST00000318388.11	c.54+264_54+265dupAT		intron_variant	Intron 1 of 7	1	NM_021074.5	ENSP00000327268.6

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 147 AN: 151252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00122 AC: 6 AN: 4906 AF XY: 0.00150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000580 AC: 186 AN: 320944 Hom.: 0 Cov.: 0 AF XY: 0.000617 AC XY: 103 AN XY: 166968

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00386 AC: 28 AN: 7254

American (AMR) AF: 0.000958 AC: 9 AN: 9392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10562

East Asian (EAS) AF: 0.00290 AC: 66 AN: 22722

South Asian (SAS) AF: 0.000330 AC: 8 AN: 24220

European-Finnish (FIN) AF: 0.000352 AC: 9 AN: 25584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1544

European-Non Finnish (NFE) AF: 0.000290 AC: 58 AN: 199732

Other (OTH) AF: 0.000401 AC: 8 AN: 19934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000971 AC: 147 AN: 151358 Hom.: 0 Cov.: 32 AF XY: 0.000974 AC XY: 72 AN XY: 73910

African (AFR) AF: 0.00285 AC: 118 AN: 41354

American (AMR) AF: 0.000197 AC: 3 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5154

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4802

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67696

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000123 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs148124234; hg19: chr18-9103046;