rs11576415

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency, nuclear type 6
Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome with cardiomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leber hereditary optic neuropathy
Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

NDUFS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NDUFS2	NM_001377299.1 link	c.1054C>G	p.Pro352Ala	missense_variant	Exon 10 of 14	ENST00000676972.1	NP_001364228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS2	ENST00000676972.1 link	c.1054C>G	p.Pro352Ala	missense_variant	Exon 10 of 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

GnomAD2 exomes

AF:

0.0756

AC:

19013

AN:

251334

AF XY:

0.0793

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 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

African (AFR)

AF:

0.0144

AC:

481

AN:

33474

American (AMR)

AF:

0.0420

AC:

1877

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0542

AC:

1417

AN:

26134

East Asian (EAS)

AF:

0.0134

AC:

531

AN:

39692

South Asian (SAS)

AF:

0.0915

AC:

7890

AN:

86250

European-Finnish (FIN)

AF:

0.101

AC:

5364

AN:

53354

Middle Eastern (MID)

AF:

0.0569

AC:

328

AN:

5768

European-Non Finnish (NFE)

AF:

0.0991

AC:

110149

AN:

1111826

Other (OTH)

AF:

0.0795

AC:

4802

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

6617

13234

19851

26468

33085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3978

7956

11934

15912

19890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0652

AC:

9919

AN:

152162

Hom.:

410

Cov.:

AF XY:

0.0646

AC XY:

4805

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0171

AC:

709

AN:

41518

American (AMR)

AF:

0.0485

AC:

741

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0569

AC:

197

AN:

3462

East Asian (EAS)

AF:

0.00908

AC:

AN:

5174

South Asian (SAS)

AF:

0.0896

AC:

432

AN:

4822

European-Finnish (FIN)

AF:

0.0964

AC:

1019

AN:

10570

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0964

AC:

6554

AN:

68006

Other (OTH)

AF:

0.0607

AC:

128

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

448

895

1343

1790

2238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 I deficiency, nuclear type 6

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

7.3

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

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over