18-9103048-GATAT-GAT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_021074.5(NDUFV2):​c.54+264_54+265delAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00655 in 382,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: NDUFV2 NM_021074.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0640
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0139) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).
• BP6: Variant 18-9103048-GAT-G is Benign according to our data. Variant chr18-9103048-GAT-G is described in ClinVar as [Benign]. Clinvar id is 1267616.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5	c.54+264_54+265delAT		intron_variant	Intron 1 of 7	ENST00000318388.11	NP_066552.2
NDUFV2	XR_243808.4	n.99+264_99+265delAT		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+265delAT		intron_variant	Intron 1 of 7	1	NM_021074.5	ENSP00000327268.6

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 151114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0481 AC: 236 AN: 4906 AF XY: 0.0488

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.0423

Gnomad ASJ exome AF: 0.0660

Gnomad EAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0599

Gnomad OTH exome AF: 0.0579

GnomAD4 exome AF: 0.0108 AC: 2503 AN: 231094 Hom.: 0 AF XY: 0.0110 AC XY: 1332 AN XY: 121080

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

African (AFR) AF: 0.00868 AC: 40 AN: 4606

American (AMR) AF: 0.0150 AC: 99 AN: 6604

Ashkenazi Jewish (ASJ) AF: 0.00897 AC: 64 AN: 7138

East Asian (EAS) AF: 0.00715 AC: 104 AN: 14538

South Asian (SAS) AF: 0.0152 AC: 345 AN: 22736

European-Finnish (FIN) AF: 0.00839 AC: 160 AN: 19072

Middle Eastern (MID) AF: 0.00973 AC: 10 AN: 1028

European-Non Finnish (NFE) AF: 0.0109 AC: 1544 AN: 141398

Other (OTH) AF: 0.00980 AC: 137 AN: 13974

⚠️ 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: 0.0000198 AC: 3 AN: 151216 Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3 AN XY: 73822

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15196

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10336

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

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67650

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.064
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs148124234; hg19: chr18-9103046; COSMIC: COSV59187212; COSMIC: COSV59187212;