chr1-161212418-C-G

Variant names:

• chr1-161212418-C-G
• rs11576415
• NM_001377299.1:c.1054C>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.1054C>G​(p.Pro352Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 1,613,760 control chromosomes in the GnomAD database, including 6,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (410 hom., cov: 31)
  • Exomes 𝑓: 0.091 (6490 hom.)
• Consequence: NDUFS2 NM_001377299.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.31
• Publications: 37 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 disease

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

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 (MetaRNN=0.0036414862).
• BP6: Variant 1-161212418-C-G is Benign according to our data. Variant chr1-161212418-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0944 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.1054C>G	p.Pro352Ala	missense	Exon 10 of 14	NP_001364228.1	O75306-1
	NDUFS2	NM_001377298.1		c.1054C>G	p.Pro352Ala	missense	Exon 11 of 15	NP_001364227.1	O75306-1
	NDUFS2	NM_004550.5		c.1054C>G	p.Pro352Ala	missense	Exon 11 of 15	NP_004541.1	O75306-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000676972.1	MANE Select	c.1054C>G	p.Pro352Ala	missense	Exon 10 of 14	ENSP00000503117.1	O75306-1
	NDUFS2	ENST00000367993.7	TSL:1	c.1054C>G	p.Pro352Ala	missense	Exon 11 of 15	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000392179.5	TSL:1	c.1054C>G	p.Pro352Ala	missense	Exon 10 of 13	ENSP00000376018.4	O75306-2

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9921 AN: 152044 Hom.: 410 Cov.: 31

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0569

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.0893

Gnomad FIN AF: 0.0964

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0964

Gnomad OTH AF: 0.0608

GnomAD2 exomes AF: 0.0756 AC: 19013 AN: 251334 AF XY: 0.0793

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.0102

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0979

Gnomad OTH exome AF: 0.0817

GnomAD4 exome AF: 0.0909 AC: 132839 AN: 1461598 Hom.: 6490 Cov.: 32 AF XY: 0.0905 AC XY: 65810 AN XY: 727112

African (AFR) AF: 0.0144 AC: 481 AN: 33474

American (AMR) AF: 0.0420 AC: 1877 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 1417 AN: 26134

East Asian (EAS) AF: 0.0134 AC: 531 AN: 39692

South Asian (SAS) AF: 0.0915 AC: 7890 AN: 86250

European-Finnish (FIN) AF: 0.101 AC: 5364 AN: 53354

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5768

European-Non Finnish (NFE) AF: 0.0991 AC: 110149 AN: 1111826

Other (OTH) AF: 0.0795 AC: 4802 AN: 60382

GnomAD4 genome AF: 0.0652 AC: 9919 AN: 152162 Hom.: 410 Cov.: 31 AF XY: 0.0646 AC XY: 4805 AN XY: 74380

African (AFR) AF: 0.0171 AC: 709 AN: 41518

American (AMR) AF: 0.0485 AC: 741 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 197 AN: 3462

East Asian (EAS) AF: 0.00908 AC: 47 AN: 5174

South Asian (SAS) AF: 0.0896 AC: 432 AN: 4822

European-Finnish (FIN) AF: 0.0964 AC: 1019 AN: 10570

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0964 AC: 6554 AN: 68006

Other (OTH) AF: 0.0607 AC: 128 AN: 2110

Alfa AF: 0.0876 Hom.: 499

Bravo AF: 0.0594

TwinsUK AF: 0.104 AC: 384

ALSPAC AF: 0.0970 AC: 374

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.0945 AC: 813

ExAC AF: 0.0784 AC: 9524

Asia WGS AF: 0.0410 AC: 141 AN: 3478

EpiCase AF: 0.0947

EpiControl AF: 0.0903

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0036	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.017	D
Polyphen		0.83	P
Vest4		0.26
MPC		1.4
ClinPred		0.055	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.68
Mutation Taster		=90/10	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: rs11576415; hg19: chr1-161182208; COSMIC: COSV57154478; COSMIC: COSV57154478;