1-161213726-C-T

Variant names:

• chr1-161213726-C-T
• rs1136207
• NM_001377299.1:c.1290C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001377299.1(NDUFS2):​c.1290C>T​(p.Ala430Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,613,872 control chromosomes in the GnomAD database, including 17,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1468 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15781 hom.)
• Consequence: NDUFS2 NM_001377299.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.570
• Publications: 30 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 1-161213726-C-T is Benign according to our data. Variant chr1-161213726-C-T is described in ClinVar as Benign. ClinVar VariationId is 129698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377299.1. 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.1290C>T	p.Ala430Ala	synonymous	Exon 12 of 14	NP_001364228.1
	NDUFS2	NM_001377298.1		c.1290C>T	p.Ala430Ala	synonymous	Exon 13 of 15	NP_001364227.1
	NDUFS2	NM_004550.5		c.1290C>T	p.Ala430Ala	synonymous	Exon 13 of 15	NP_004541.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000676972.1	MANE Select	c.1290C>T	p.Ala430Ala	synonymous	Exon 12 of 14	ENSP00000503117.1
	NDUFS2	ENST00000367993.7	TSL:1	c.1290C>T	p.Ala430Ala	synonymous	Exon 13 of 15	ENSP00000356972.3
	NDUFS2	ENST00000392179.5	TSL:1	c.1290C>T	p.Ala430Ala	synonymous	Exon 12 of 13	ENSP00000376018.4

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18768 AN: 152028 Hom.: 1472 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.158 AC: 39670 AN: 251470 AF XY: 0.152

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.333

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.139 AC: 203756 AN: 1461726 Hom.: 15781 Cov.: 32 AF XY: 0.139 AC XY: 100810 AN XY: 727168

African (AFR) AF: 0.0401 AC: 1342 AN: 33480

American (AMR) AF: 0.248 AC: 11095 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4870 AN: 26136

East Asian (EAS) AF: 0.325 AC: 12897 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8851 AN: 86252

European-Finnish (FIN) AF: 0.109 AC: 5829 AN: 53420

Middle Eastern (MID) AF: 0.156 AC: 899 AN: 5768

European-Non Finnish (NFE) AF: 0.134 AC: 149219 AN: 1111858

Other (OTH) AF: 0.145 AC: 8754 AN: 60388

GnomAD4 genome AF: 0.123 AC: 18764 AN: 152146 Hom.: 1468 Cov.: 32 AF XY: 0.125 AC XY: 9271 AN XY: 74372

African (AFR) AF: 0.0478 AC: 1985 AN: 41542

American (AMR) AF: 0.203 AC: 3098 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1702 AN: 5164

South Asian (SAS) AF: 0.0968 AC: 467 AN: 4822

European-Finnish (FIN) AF: 0.114 AC: 1202 AN: 10570

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9260 AN: 67996

Other (OTH) AF: 0.129 AC: 273 AN: 2114

Alfa AF: 0.141 Hom.: 3083

Bravo AF: 0.130

Asia WGS AF: 0.204 AC: 708 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.146

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	7.9
DANN	Benign	0.80
PhyloP100		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1136207; hg19: chr1-161183516; COSMIC: COSV57154020; COSMIC: COSV57154020;