chr9-32572946-T-C

Position:

• chr9-32572946-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002493.5(NDUFB6):​c.115A>G​(p.Lys39Glu) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB6 NM_002493.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

Genes affected

NDUFB6 (HGNC:7701): (NADH:ubiquinone oxidoreductase subunit B6) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing occurs at this locus and three transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jan 2011]

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=0.113149524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB6	NM_002493.5	c.115A>G	p.Lys39Glu	missense_variant	1/4	ENST00000379847.8	NP_002484.1
NDUFB6	NM_182739.3	c.115A>G	p.Lys39Glu	missense_variant	1/3		NP_877416.1
NDUFB6	NM_001199987.2	c.115A>G	p.Lys39Glu	missense_variant	1/3		NP_001186916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB6	ENST00000379847.8	c.115A>G	p.Lys39Glu	missense_variant	1/4	1	NM_002493.5	ENSP00000369176.3
NDUFB6	ENST00000350021.2	c.115A>G	p.Lys39Glu	missense_variant	1/3	2		ENSP00000297983.3
NDUFB6	ENST00000366466.5	c.115A>G	p.Lys39Glu	missense_variant	1/3	2		ENSP00000482941.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2024

The c.115A>G (p.K39E) alteration is located in exon 1 (coding exon 1) of the NDUFB6 gene. This alteration results from a A to G substitution at nucleotide position 115, causing the lysine (K) at amino acid position 39 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.054
Sift	Benign	0.054	T;.;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.062	B;.;.
Vest4		0.17
MutPred		0.41		Loss of methylation at K39 (P = 0.0042);Loss of methylation at K39 (P = 0.0042);Loss of methylation at K39 (P = 0.0042);
MVP		0.51
MPC		0.19
ClinPred		0.36	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs1157138054; hg19: chr9-32572944;