dbSNP rs3813624: NDUFS2:c.-239-960C>T (chr1-161201187-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The ENST00000367993.7(NDUFS2):c.-239-960C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,260 control chromosomes in the GnomAD database, including 1,451 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1451 hom., cov: 32)

Consequence

NDUFS2
ENST00000367993.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.148

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
NDUFS2	NM_001377298.1 link	c.-239-960C>T	intron_variant	Intron 1 of 14	NP_001364227.1
NDUFS2	NM_004550.5 link	c.-239-960C>T	intron_variant	Intron 1 of 14	NP_004541.1	O75306-1
NDUFS2	NM_001377300.1 link	c.-239-960C>T	intron_variant	Intron 1 of 13	NP_001364229.1
NDUFS2	NM_001377301.1 link	c.-239-960C>T	intron_variant	Intron 1 of 13	NP_001364230.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NDUFS2	ENST00000367993.7 link	c.-239-960C>T	intron_variant	Intron 1 of 14	1	ENSP00000356972.3	O75306-1
NDUFS2	ENST00000677846.1 link	c.-239-960C>T	intron_variant	Intron 1 of 15		ENSP00000504065.1	A0A7I2YQG7
NDUFS2	ENST00000677579.1 link	c.-239-960C>T	intron_variant	Intron 1 of 14		ENSP00000504162.1	A0A7I2V596

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18653

AN:

152142

Hom.:

1455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0481

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.328

Gnomad SAS

AF:

0.0985

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.128

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.122

AC:

18648

AN:

152260

Hom.:

1451

Cov.:

AF XY:

0.123

AC XY:

9186

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0482

AC:

2004

AN:

41564

American (AMR)

AF:

0.202

AC:

3093

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

606

AN:

3472

East Asian (EAS)

AF:

0.328

AC:

1699

AN:

5186

South Asian (SAS)

AF:

0.0969

AC:

468

AN:

4828

European-Finnish (FIN)

AF:

0.103

AC:

1091

AN:

10604

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9245

AN:

68006

Other (OTH)

AF:

0.129

AC:

271

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

846

1692

2539

3385

4231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.135

Hom.:

275

Bravo

AF:

0.129

Asia WGS

AF:

0.203

AC:

704

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over