rs35086265

Variant names:

• chr1-161210692-G-A
• rs35086265
• NM_001377299.1:c.968G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-161210692-G-A
• chr1-161210692-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001377299.1(NDUFS2):​c.968G>A​(p.Arg323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,613,978 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R323R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (27 hom.)
• Consequence: NDUFS2 NM_001377299.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.702
• Publications: 5 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013175368).
• BP6: Variant 1-161210692-G-A is Benign according to our data. Variant chr1-161210692-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214787.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00463 (704/152160) while in subpopulation AMR AF = 0.00943 (144/15272). AF 95% confidence interval is 0.00817. There are 5 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Mitochondrial,Unknown gene

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.968G>A	p.Arg323Gln	missense	Exon 9 of 14	NP_001364228.1	O75306-1
	NDUFS2	NM_001377298.1		c.968G>A	p.Arg323Gln	missense	Exon 10 of 15	NP_001364227.1	O75306-1
	NDUFS2	NM_004550.5		c.968G>A	p.Arg323Gln	missense	Exon 10 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.968G>A	p.Arg323Gln	missense	Exon 9 of 14	ENSP00000503117.1	O75306-1
	NDUFS2	ENST00000367993.7	TSL:1	c.968G>A	p.Arg323Gln	missense	Exon 10 of 15	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000392179.5	TSL:1	c.968G>A	p.Arg323Gln	missense	Exon 9 of 13	ENSP00000376018.4	O75306-2

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 704 AN: 152042 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00481 AC: 1209 AN: 251458 AF XY: 0.00482

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00520 AC: 7605 AN: 1461818 Hom.: 27 Cov.: 32 AF XY: 0.00509 AC XY: 3703 AN XY: 727208

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.00519 AC: 232 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00342 AC: 295 AN: 86248

European-Finnish (FIN) AF: 0.0146 AC: 779 AN: 53404

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.00522 AC: 5810 AN: 1111976

Other (OTH) AF: 0.00475 AC: 287 AN: 60394

GnomAD4 genome AF: 0.00463 AC: 704 AN: 152160 Hom.: 5 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74392

African (AFR) AF: 0.00104 AC: 43 AN: 41508

American (AMR) AF: 0.00943 AC: 144 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00333 AC: 16 AN: 4810

European-Finnish (FIN) AF: 0.0173 AC: 183 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 67998

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00408 Hom.: 3

Bravo AF: 0.00370

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00422 AC: 513

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00486

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Mitochondrial complex I deficiency, nuclear type 6 (2)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	NDUFS2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.70
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.53
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.063	B
Vest4		0.69
MVP		0.92
MPC		0.59
ClinPred		0.0039	T
GERP RS		-0.045
Varity_R		0.11
gMVP		0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35086265; hg19: chr1-161180482; COSMIC: COSV99248123; COSMIC: COSV99248123;