rs1136224

Positions:

• chr1-161214307-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377299.1(NDUFS2):​c.*114A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 900,098 control chromosomes in the GnomAD database, including 15,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1776 hom., cov: 30)
  • Exomes 𝑓: 0.19 (13998 hom.)
• Consequence: NDUFS2 NM_001377299.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.836

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-161214307-A-G is Benign according to our data. Variant chr1-161214307-A-G is described in ClinVar as [Benign]. Clinvar id is 293289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS2	NM_001377299.1	c.*114A>G		3_prime_UTR_variant	14/14	ENST00000676972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS2	ENST00000676972.1	c.*114A>G		3_prime_UTR_variant	14/14		NM_001377299.1	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 20411 AN: 143926 Hom.: 1776 Cov.: 30

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.194 AC: 146600 AN: 756068 Hom.: 13998 Cov.: 11 AF XY: 0.198 AC XY: 77343 AN XY: 390656

Gnomad4 AFR exome AF: 0.0476

Gnomad4 AMR exome AF: 0.305

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.336

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.142 AC: 20419 AN: 144030 Hom.: 1776 Cov.: 30 AF XY: 0.149 AC XY: 10427 AN XY: 70138

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.159

Alfa AF: 0.151 Hom.: 2735

Bravo AF: 0.133

Asia WGS AF: 0.282 AC: 979 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex 1 deficiency, nuclear type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.99
DANN	Benign	0.50
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2

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: rs1136224; hg19: chr1-161184097;