rs878853093

Positions:

• chr1-161210144-C-A
• chr1-161210144-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 15/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS2	NM_001377299.1	c.736C>A	p.Gln246Lys	missense_variant	7/14	ENST00000676972.1	NP_001364228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS2	ENST00000676972.1	c.736C>A	p.Gln246Lys	missense_variant	7/14		NM_001377299.1	ENSP00000503117	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Apr 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.22
Sift	Benign	0.89	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.0	B;.
Vest4		0.18
MutPred		0.42		Gain of ubiquitination at Q246 (P = 0.0337);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853093; hg19: chr1-161179934;