rs2075626

Variant names:

• chr11-68032459-T-C
• rs2075626
• NM_002496.4:c.109+123T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002496.4(NDUFS8):​c.109+123T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,561,342 control chromosomes in the GnomAD database, including 40,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3881 hom., cov: 33)
  • Exomes 𝑓: 0.23 (36746 hom.)
• Consequence: NDUFS8 NM_002496.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630
• Publications: 35 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)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 11-68032459-T-C is Benign according to our data. Variant chr11-68032459-T-C is described in ClinVar as Benign. ClinVar VariationId is 1288362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS8	NM_002496.4	c.109+123T>C		intron_variant	Intron 3 of 6	ENST00000313468.10	NP_002487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS8	ENST00000313468.10	c.109+123T>C		intron_variant	Intron 3 of 6	1	NM_002496.4	ENSP00000315774.5

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33698 AN: 152012 Hom.: 3880 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0962

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.225 AC: 317390 AN: 1409212 Hom.: 36746 Cov.: 38 AF XY: 0.224 AC XY: 155813 AN XY: 696896

African (AFR) AF: 0.252 AC: 8100 AN: 32154

American (AMR) AF: 0.127 AC: 4717 AN: 37270

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5909 AN: 25350

East Asian (EAS) AF: 0.224 AC: 8274 AN: 36952

South Asian (SAS) AF: 0.154 AC: 12561 AN: 81574

European-Finnish (FIN) AF: 0.119 AC: 5558 AN: 46834

Middle Eastern (MID) AF: 0.221 AC: 903 AN: 4092

European-Non Finnish (NFE) AF: 0.238 AC: 258388 AN: 1086580

Other (OTH) AF: 0.222 AC: 12980 AN: 58406

GnomAD4 genome AF: 0.222 AC: 33713 AN: 152130 Hom.: 3881 Cov.: 33 AF XY: 0.213 AC XY: 15855 AN XY: 74386

African (AFR) AF: 0.254 AC: 10536 AN: 41486

American (AMR) AF: 0.172 AC: 2634 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 760 AN: 3470

East Asian (EAS) AF: 0.218 AC: 1126 AN: 5168

South Asian (SAS) AF: 0.155 AC: 748 AN: 4828

European-Finnish (FIN) AF: 0.0962 AC: 1021 AN: 10610

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16089 AN: 67970

Other (OTH) AF: 0.227 AC: 480 AN: 2110

Alfa AF: 0.228 Hom.: 7339

Bravo AF: 0.229

Asia WGS AF: 0.189 AC: 661 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.5
DANN	Benign	0.76
PhyloP100		0.063
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: rs2075626; hg19: chr11-67799926; COSMIC: COSV50292376; COSMIC: COSV50292376;