rs4656994

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.703-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,610,726 control chromosomes in the GnomAD database, including 42,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.22 ( 3936 hom., cov: 31)

Exomes 𝑓: 0.23 ( 38789 hom. )

Consequence

NDUFS2
NM_001377299.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.24

Publications

38 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-161210087-G-A is Benign according to our data. Variant chr1-161210087-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS2	NM_001377299.1 link	c.703-24G>A		intron_variant	Intron 6 of 13	ENST00000676972.1	NP_001364228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS2	ENST00000676972.1 link	c.703-24G>A		intron_variant	Intron 6 of 13		NM_001377299.1	ENSP00000503117.1		O75306-1

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33822

AN:

151962

Hom.:

3928

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.214

GnomAD2 exomes

AF:

0.250

AC:

62934

AN:

251432

AF XY:

0.249

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.337

Gnomad ASJ exome

AF:

0.264

Gnomad EAS exome

AF:

0.393

Gnomad FIN exome

AF:

0.174

Gnomad NFE exome

AF:

0.216

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.226

AC:

329674

AN:

1458646

Hom.:

38789

Cov.:

AF XY:

0.227

AC XY:

164947

AN XY:

725834

show subpopulations

African (AFR)

AF:

0.191

AC:

6366

AN:

33408

American (AMR)

AF:

0.331

AC:

14794

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

6879

AN:

26122

East Asian (EAS)

AF:

0.410

AC:

16286

AN:

39680

South Asian (SAS)

AF:

0.272

AC:

23404

AN:

86172

European-Finnish (FIN)

AF:

0.176

AC:

9404

AN:

53406

Middle Eastern (MID)

AF:

0.263

AC:

1516

AN:

5762

European-Non Finnish (NFE)

AF:

0.213

AC:

236593

AN:

1109102

Other (OTH)

AF:

0.239

AC:

14432

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

14512

29024

43536

58048

72560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8376

16752

25128

33504

41880

<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:

0.223

AC:

33860

AN:

152080

Hom.:

3936

Cov.:

AF XY:

0.225

AC XY:

16731

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.196

AC:

8108

AN:

41464

American (AMR)

AF:

0.289

AC:

4415

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

860

AN:

3472

East Asian (EAS)

AF:

0.398

AC:

2056

AN:

5160

South Asian (SAS)

AF:

0.261

AC:

1257

AN:

4822

European-Finnish (FIN)

AF:

0.179

AC:

1891

AN:

10574

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.214

AC:

14552

AN:

67994

Other (OTH)

AF:

0.214

AC:

452

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1321

2641

3962

5282

6603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.227

Hom.:

7677

Bravo

AF:

0.229

Asia WGS

AF:

0.337

AC:

1170

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.21

(source)

DANN

Benign

0.43

PhyloP100

-1.2

BranchPoint Hunter

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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