rs150278938

Variant names:

• chr11-68032155-C-T
• rs150278938
• NM_002496.4:c.4C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_002496.4(NDUFS8):​c.4C>T​(p.Arg2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,612,352 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: NDUFS8 NM_002496.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: -0.312
• Publications: 7 publications found

Genes affected

NDUFS8 (HGNC:7715): (NADH:ubiquinone oxidoreductase core subunit S8) This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. Mutations in this gene have been associated with Leigh syndrome. [provided by RefSeq, Mar 2010]

NDUFS8 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.74371 (below the threshold of 3.09). Trascript score misZ: 1.1202 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, nuclear type 2, mitochondrial disease, Leigh syndrome, Leigh syndrome with leukodystrophy, mitochondrial complex I deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014999539).
• BP6: Variant 11-68032155-C-T is Benign according to our data. Variant chr11-68032155-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214836.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00192 (292/152366) while in subpopulation NFE AF = 0.00322 (219/68036). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002496.4. 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
	NDUFS8	NM_002496.4	MANE Select	c.4C>T	p.Arg2Cys	missense	Exon 2 of 7	NP_002487.1	O00217

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	ENST00000313468.10	TSL:1 MANE Select	c.4C>T	p.Arg2Cys	missense	Exon 2 of 7	ENSP00000315774.5	O00217
	NDUFS8	ENST00000528492.1	TSL:1	c.-67+1422C>T		intron	N/A	ENSP00000432848.1	Q08E91
	NDUFS8	ENST00000852151.1		c.4C>T	p.Arg2Cys	missense	Exon 2 of 7	ENSP00000522210.1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00166 AC: 417 AN: 251298 AF XY: 0.00168

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00277 AC: 4041 AN: 1459986 Hom.: 7 Cov.: 31 AF XY: 0.00267 AC XY: 1936 AN XY: 726268

African (AFR) AF: 0.000658 AC: 22 AN: 33422

American (AMR) AF: 0.000894 AC: 40 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86172

European-Finnish (FIN) AF: 0.000807 AC: 43 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4370

European-Non Finnish (NFE) AF: 0.00339 AC: 3768 AN: 1111962

Other (OTH) AF: 0.00249 AC: 150 AN: 60230

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74508

African (AFR) AF: 0.000721 AC: 30 AN: 41588

American (AMR) AF: 0.00157 AC: 24 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00256 Hom.: 6

Bravo AF: 0.00195

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00151 AC: 183

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	2	-	Leigh syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 2 (1)
-	-	1	NDUFS8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Benign	0.0	N
PhyloP100		-0.31
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Polyphen		0.83	P
Vest4		0.38
MVP		0.96
MPC		0.67
ClinPred		0.032	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.53
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs150278938; hg19: chr11-67799622; COSMIC: COSV50288755; COSMIC: COSV50288755;