rs752670374

Positions:

chr18-9117903-GGTAA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000318388.11(NDUFV2):c.120+5_120+8del variant causes a splice donor, splice donor region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,583,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

NDUFV2
ENST00000318388.11 splice_donor, splice_donor_region, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.71

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.086666666 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 0 (no position change), new splice context is: gtgGTaatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-9117903-GGTAA-G is Pathogenic according to our data. Variant chr18-9117903-GGTAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 279920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
NDUFV2	NM_021074.5 linkuse as main transcript	c.120+5_120+8del	splice_donor_variant, splice_donor_region_variant, intron_variant	ENST00000318388.11	NP_066552.2
NDUFV2	XM_017025782.2 linkuse as main transcript	c.33+5_33+8del	splice_donor_variant, splice_donor_region_variant, intron_variant		XP_016881271.1
NDUFV2	XR_243808.4 linkuse as main transcript	n.165+5_165+8del	splice_donor_variant, splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFV2	ENST00000318388.11 linkuse as main transcript	c.120+5_120+8del		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_021074.5	ENSP00000327268	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251128

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135788

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000559

AC:

AN:

1431300

Hom.:

AF XY:

0.00000700

AC XY:

AN XY:

714236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000369

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 7

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pediatrics, Government Thiruvarur Medical College and Hospital	Oct 14, 2024	The splice donor c.120+5_120+8del variant in NDUFV2 gene has been reported previously in individual(s) affected with NDUFV2 related disorders (Bénit et al., 2003) as hypertropic cardiomyopathy and encephalopathy.This is the first reported case from INDIA with NDUFV2 gene mutation and the second case of NDUFV2:c.120+5_120+8del mutation presenting without cardiomyopathy. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2022

Published functional studies indicate that c.120+5_120+8delGTAA causes a significant reduction in the mitochondrial targeting ability of the NDUFV2 protein (Liu et al., 2011); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29554876, 11220739, 12754703, 26008862, 27126960, 30831263, 21548921) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.45

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over