chr1-161207016-A-G

Variant names:

• chr1-161207016-A-G
• rs16832694
• NM_001377299.1:c.393+419A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377299.1(NDUFS2):​c.393+419A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 152,278 control chromosomes in the GnomAD database, including 445 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 0.072 (445 hom., cov: 31)
• Consequence: NDUFS2 NM_001377299.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377299.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	NM_001377299.1	MANE Select	c.393+419A>G		intron	N/A	NP_001364228.1
	NDUFS2	NM_001377298.1		c.393+419A>G		intron	N/A	NP_001364227.1
	NDUFS2	NM_004550.5		c.393+419A>G		intron	N/A	NP_004541.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000676972.1	MANE Select	c.393+419A>G		intron	N/A	ENSP00000503117.1
	NDUFS2	ENST00000367993.7	TSL:1	c.393+419A>G		intron	N/A	ENSP00000356972.3
	NDUFS2	ENST00000392179.5	TSL:1	c.393+419A>G		intron	N/A	ENSP00000376018.4

Frequencies

GnomAD3 genomes AF: 0.0716 AC: 10890 AN: 152160 Hom.: 439 Cov.: 31

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.0706

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0739

Gnomad OTH AF: 0.0641

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

GnomAD4 genome AF: 0.0718 AC: 10926 AN: 152278 Hom.: 445 Cov.: 31 AF XY: 0.0731 AC XY: 5447 AN XY: 74464

African (AFR) AF: 0.0638 AC: 2654 AN: 41568

American (AMR) AF: 0.0739 AC: 1130 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3472

East Asian (EAS) AF: 0.0705 AC: 366 AN: 5188

South Asian (SAS) AF: 0.144 AC: 693 AN: 4828

European-Finnish (FIN) AF: 0.0641 AC: 680 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0740 AC: 5029 AN: 68002

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0710 Hom.: 74

Bravo AF: 0.0688

Asia WGS AF: 0.126 AC: 438 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.66
DANN	Benign	0.84
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16832694; hg19: chr1-161176806;