NM_001377299.1:c.736C>A

Variant names:

• chr1-161210144-C-A
• rs878853093
• NM_001377299.1:c.736C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377299.1(NDUFS2):​c.736C>A​(p.Gln246Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFS2 NM_001377299.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 0 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 disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 6

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09967843).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	NM_001377299.1	MANE Select	c.736C>A	p.Gln246Lys	missense	Exon 7 of 14	NP_001364228.1	O75306-1
	NDUFS2	NM_001377298.1		c.736C>A	p.Gln246Lys	missense	Exon 8 of 15	NP_001364227.1	O75306-1
	NDUFS2	NM_004550.5		c.736C>A	p.Gln246Lys	missense	Exon 8 of 15	NP_004541.1	O75306-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000676972.1	MANE Select	c.736C>A	p.Gln246Lys	missense	Exon 7 of 14	ENSP00000503117.1	O75306-1
	NDUFS2	ENST00000367993.7	TSL:1	c.736C>A	p.Gln246Lys	missense	Exon 8 of 15	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000392179.5	TSL:1	c.736C>A	p.Gln246Lys	missense	Exon 7 of 13	ENSP00000376018.4	O75306-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	N
PhyloP100		3.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.22
Sift	Benign	0.89	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.42		Gain of ubiquitination at Q246 (P = 0.0337)
MVP		0.52
MPC		0.65
ClinPred		0.48	T
GERP RS		-0.14
Varity_R		0.31
gMVP		0.84
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878853093; hg19: chr1-161179934;