rs11538340

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.58C>A(p.Pro20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0826 in 1,612,070 control chromosomes in the GnomAD database, including 6,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.075 ( 480 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5624 hom. )

Consequence

NDUFS2
NM_001377299.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.378

Publications

29 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=0.0016286671).

BP6

Variant 1-161202443-C-A is Benign according to our data. Variant chr1-161202443-C-A is described in ClinVar as Benign. ClinVar VariationId is 293269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS2	NM_001377299.1 link	c.58C>A	p.Pro20Thr	missense_variant	Exon 1 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.58C>A	p.Pro20Thr	missense_variant	Exon 1 of 14		NM_001377299.1	ENSP00000503117.1		O75306-1

Frequencies

GnomAD3 genomes

AF:

0.0747

AC:

11363

AN:

152046

Hom.:

474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0648

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0765

Gnomad ASJ

AF:

0.0594

Gnomad EAS

AF:

0.0703

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.0642

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0771

Gnomad OTH

AF:

0.0679

GnomAD2 exomes

AF:

0.0854

AC:

20855

AN:

244234

AF XY:

0.0906

show subpopulations

Gnomad AFR exome

AF:

0.0658

Gnomad AMR exome

AF:

0.0780

Gnomad ASJ exome

AF:

0.0623

Gnomad EAS exome

AF:

0.0618

Gnomad FIN exome

AF:

0.0651

Gnomad NFE exome

AF:

0.0781

Gnomad OTH exome

AF:

0.0779

GnomAD4 exome

AF:

0.0834

AC:

121744

AN:

1459906

Hom.:

5624

Cov.:

AF XY:

0.0857

AC XY:

62253

AN XY:

726090

show subpopulations

African (AFR)

AF:

0.0627

AC:

2099

AN:

33466

American (AMR)

AF:

0.0773

AC:

3441

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.0627

AC:

1633

AN:

26064

East Asian (EAS)

AF:

0.0867

AC:

3436

AN:

39652

South Asian (SAS)

AF:

0.169

AC:

14500

AN:

85740

European-Finnish (FIN)

AF:

0.0669

AC:

3545

AN:

53000

Middle Eastern (MID)

AF:

0.0946

AC:

544

AN:

5752

European-Non Finnish (NFE)

AF:

0.0786

AC:

87316

AN:

1111430

Other (OTH)

AF:

0.0868

AC:

5230

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

6703

13407

20110

26814

33517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3368

6736

10104

13472

16840

<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:

0.0749

AC:

11397

AN:

152164

Hom.:

480

Cov.:

AF XY:

0.0767

AC XY:

5703

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0650

AC:

2698

AN:

41502

American (AMR)

AF:

0.0774

AC:

1184

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0594

AC:

206

AN:

3468

East Asian (EAS)

AF:

0.0703

AC:

364

AN:

5178

South Asian (SAS)

AF:

0.163

AC:

786

AN:

4818

European-Finnish (FIN)

AF:

0.0642

AC:

681

AN:

10604

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0772

AC:

5246

AN:

67980

Other (OTH)

AF:

0.0677

AC:

143

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

526

1052

1579

2105

2631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0723

Hom.:

1504

Bravo

AF:

0.0718

TwinsUK

AF:

0.0769

AC:

285

ALSPAC

AF:

0.0861

AC:

332

ESP6500AA

AF:

0.0640

AC:

282

ESP6500EA

AF:

0.0792

AC:

681

ExAC

AF:

0.0865

AC:

10501

Asia WGS

AF:

0.132

AC:

457

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27779215) -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 6

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.051

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

L;L

PhyloP100

0.38

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.19

Sift

Benign

0.046

D;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0010

B;.

Vest4

0.11

MPC

0.57

ClinPred

0.0062

GERP RS

3.8

PromoterAI

-0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.059

gMVP

0.30

Mutation Taster

=97/3

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