1-161214307-A-G

Variant names:

• chr1-161214307-A-G
• rs1136224
• NM_001377299.1:c.*114A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 39 publications found

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]

NDUFS2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 6

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial 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=-0.87).
• BP6: Variant 1-161214307-A-G is Benign according to our data. Variant chr1-161214307-A-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NDUFS2	NM_001377299.1	c.*114A>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000676972.1	NP_001364228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS2	ENST00000676972.1	c.*114A>G		3_prime_UTR_variant	Exon 14 of 14		NM_001377299.1	ENSP00000503117.1

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

African (AFR) AF: 0.0476 AC: 894 AN: 18798

American (AMR) AF: 0.305 AC: 9596 AN: 31458

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3016 AN: 19956

East Asian (EAS) AF: 0.336 AC: 10118 AN: 30158

South Asian (SAS) AF: 0.304 AC: 18705 AN: 61588

European-Finnish (FIN) AF: 0.209 AC: 9270 AN: 44402

Middle Eastern (MID) AF: 0.197 AC: 622 AN: 3160

European-Non Finnish (NFE) AF: 0.172 AC: 87803 AN: 511142

Other (OTH) AF: 0.186 AC: 6576 AN: 35406

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

African (AFR) AF: 0.0442 AC: 1711 AN: 38684

American (AMR) AF: 0.193 AC: 2782 AN: 14430

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 487 AN: 3424

East Asian (EAS) AF: 0.301 AC: 1425 AN: 4732

South Asian (SAS) AF: 0.295 AC: 1338 AN: 4534

European-Finnish (FIN) AF: 0.209 AC: 2062 AN: 9858

Middle Eastern (MID) AF: 0.174 AC: 49 AN: 282

European-Non Finnish (NFE) AF: 0.156 AC: 10143 AN: 65216

Other (OTH) AF: 0.159 AC: 317 AN: 1996

Alfa AF: 0.150 Hom.: 4103

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

-

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

- -

Mitochondrial complex I deficiency, nuclear type 6 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.84
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
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: rs1136224; hg19: chr1-161184097; COSMIC: COSV107324287; COSMIC: COSV107324287;