rs1136224

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_004550.5(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_004550.5 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004550.5. 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
	NDUFS2	NM_001377299.1	MANE Select	c.*114A>G		3_prime_UTR	Exon 14 of 14	NP_001364228.1
	NDUFS2	NM_001377298.1		c.*114A>G		3_prime_UTR	Exon 15 of 15	NP_001364227.1
	NDUFS2	NM_004550.5		c.*114A>G		3_prime_UTR	Exon 15 of 15	NP_004541.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000676972.1	MANE Select	c.*114A>G		3_prime_UTR	Exon 14 of 14	ENSP00000503117.1
	NDUFS2	ENST00000367993.7	TSL:1	c.*114A>G		3_prime_UTR	Exon 15 of 15	ENSP00000356972.3
	NDUFS2	ENST00000392179.5	TSL:1	c.*366A>G		3_prime_UTR	Exon 13 of 13	ENSP00000376018.4

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 6 (1)

Computational scores

Source: dbNSFP v4.9

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;