rs11576415

Positions:

chr1-161212418-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001377299.1(NDUFS2):c.1054C>G(p.Pro352Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 1,613,760 control chromosomes in the GnomAD database, including 6,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 410 hom., cov: 31)

Exomes 𝑓: 0.091 ( 6490 hom. )

Consequence

NDUFS2
NM_001377299.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.31

Variant links:

Genes affected

NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

NDUFS2 links:

NDUFS2 (HGNC:):

NDUFS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036414862).

BP6

Variant 1-161212418-C-G is Benign according to our data. Variant chr1-161212418-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS2	NM_001377299.1 linkuse as main transcript	c.1054C>G	p.Pro352Ala	missense_variant	10/14	ENST00000676972.1	NP_001364228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS2	ENST00000676972.1 linkuse as main transcript	c.1054C>G	p.Pro352Ala	missense_variant	10/14		NM_001377299.1	ENSP00000503117.1		O75306-1

Frequencies

GnomAD3 genomes

AF:

0.0653

AC:

9921

AN:

152044

Hom.:

410

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0171

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.0569

Gnomad EAS

AF:

0.00926

Gnomad SAS

AF:

0.0893

Gnomad FIN

AF:

0.0964

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0964

Gnomad OTH

AF:

0.0608

GnomAD3 exomes

AF:

0.0756

AC:

19013

AN:

251334

Hom.:

872

AF XY:

0.0793

AC XY:

10778

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.0406

Gnomad ASJ exome

AF:

0.0512

Gnomad EAS exome

AF:

0.0102

Gnomad SAS exome

AF:

0.0930

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.0979

Gnomad OTH exome

AF:

0.0817

GnomAD4 exome

AF:

0.0909

AC:

132839

AN:

1461598

Hom.:

6490

Cov.:

AF XY:

0.0905

AC XY:

65810

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0144

Gnomad4 AMR exome

AF:

0.0420

Gnomad4 ASJ exome

AF:

0.0542

Gnomad4 EAS exome

AF:

0.0134

Gnomad4 SAS exome

AF:

0.0915

Gnomad4 FIN exome

AF:

0.101

Gnomad4 NFE exome

AF:

0.0991

Gnomad4 OTH exome

AF:

0.0795

GnomAD4 genome

AF:

0.0652

AC:

9919

AN:

152162

Hom.:

410

Cov.:

AF XY:

0.0646

AC XY:

4805

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0171

Gnomad4 AMR

AF:

0.0485

Gnomad4 ASJ

AF:

0.0569

Gnomad4 EAS

AF:

0.00908

Gnomad4 SAS

AF:

0.0896

Gnomad4 FIN

AF:

0.0964

Gnomad4 NFE

AF:

0.0964

Gnomad4 OTH

AF:

0.0607

Alfa

AF:

0.0876

Hom.:

499

Bravo

AF:

0.0594

TwinsUK

AF:

0.104

AC:

384

ALSPAC

AF:

0.0970

AC:

374

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.0945

AC:

813

ExAC

AF:

0.0784

AC:

9524

Asia WGS

AF:

0.0410

AC:

141

AN:

3478

EpiCase

AF:

0.0947

EpiControl

AF:

0.0903

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mitochondrial complex 1 deficiency, nuclear type 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Mitochondrial complex I deficiency, nuclear type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.0036

T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.83

P;.

Vest4

0.26

MPC

1.4

ClinPred

0.055

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.68

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

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