rs3813624

Variant names:

• chr1-161201187-C-T
• rs3813624
• ENST00000367993.7:c.-239-960C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004550.5(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 NM_004550.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 9 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004550.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	NM_001377298.1		c.-239-960C>T		intron	N/A	NP_001364227.1	O75306-1
	NDUFS2	NM_004550.5		c.-239-960C>T		intron	N/A	NP_004541.1	O75306-1
	NDUFS2	NM_001377300.1		c.-239-960C>T		intron	N/A	NP_001364229.1	O75306-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000367993.7	TSL:1	c.-239-960C>T		intron	N/A	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000677846.1		c.-239-960C>T		intron	N/A	ENSP00000504065.1	A0A7I2YQG7
	NDUFS2	ENST00000677579.1		c.-239-960C>T		intron	N/A	ENSP00000504162.1	A0A7I2V596

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18653 AN: 152142 Hom.: 1455 Cov.: 32

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.: 32 AF XY: 0.123 AC XY: 9186 AN XY: 74434

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: 45 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9245 AN: 68006

Other (OTH) AF: 0.129 AC: 271 AN: 2108

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.15
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: rs3813624; hg19: chr1-161170977;