rs11538340

Variant names:

• chr1-161202443-C-A
• rs11538340
• NM_001377299.1:c.58C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-161202443-C-A
• chr1-161202443-C-G
• chr1-161202443-C-T

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.58C>A​(p.Pro20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0826 in 1,612,070 control chromosomes in the GnomAD database, including 6,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.075 (480 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5624 hom.)
• Consequence: NDUFS2 NM_001377299.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.378
• Publications: 29 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=0.0016286671).
• BP6: Variant 1-161202443-C-A is Benign according to our data. Variant chr1-161202443-C-A is described in ClinVar as Benign. ClinVar VariationId is 293269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 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.58C>A	p.Pro20Thr	missense	Exon 1 of 14	NP_001364228.1	O75306-1
	NDUFS2	NM_001377298.1		c.58C>A	p.Pro20Thr	missense	Exon 2 of 15	NP_001364227.1	O75306-1
	NDUFS2	NM_004550.5		c.58C>A	p.Pro20Thr	missense	Exon 2 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.58C>A	p.Pro20Thr	missense	Exon 1 of 14	ENSP00000503117.1	O75306-1
	NDUFS2	ENST00000367993.7	TSL:1	c.58C>A	p.Pro20Thr	missense	Exon 2 of 15	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000392179.5	TSL:1	c.58C>A	p.Pro20Thr	missense	Exon 1 of 13	ENSP00000376018.4	O75306-2

Frequencies

GnomAD3 genomes AF: 0.0747 AC: 11363 AN: 152046 Hom.: 474 Cov.: 32

Gnomad AFR AF: 0.0648

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.0703

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0642

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0771

Gnomad OTH AF: 0.0679

GnomAD2 exomes AF: 0.0854 AC: 20855 AN: 244234 AF XY: 0.0906

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.0780

Gnomad ASJ exome AF: 0.0623

Gnomad EAS exome AF: 0.0618

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0781

Gnomad OTH exome AF: 0.0779

GnomAD4 exome AF: 0.0834 AC: 121744 AN: 1459906 Hom.: 5624 Cov.: 31 AF XY: 0.0857 AC XY: 62253 AN XY: 726090

African (AFR) AF: 0.0627 AC: 2099 AN: 33466

American (AMR) AF: 0.0773 AC: 3441 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1633 AN: 26064

East Asian (EAS) AF: 0.0867 AC: 3436 AN: 39652

South Asian (SAS) AF: 0.169 AC: 14500 AN: 85740

European-Finnish (FIN) AF: 0.0669 AC: 3545 AN: 53000

Middle Eastern (MID) AF: 0.0946 AC: 544 AN: 5752

European-Non Finnish (NFE) AF: 0.0786 AC: 87316 AN: 1111430

Other (OTH) AF: 0.0868 AC: 5230 AN: 60284

GnomAD4 genome AF: 0.0749 AC: 11397 AN: 152164 Hom.: 480 Cov.: 32 AF XY: 0.0767 AC XY: 5703 AN XY: 74384

African (AFR) AF: 0.0650 AC: 2698 AN: 41502

American (AMR) AF: 0.0774 AC: 1184 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 206 AN: 3468

East Asian (EAS) AF: 0.0703 AC: 364 AN: 5178

South Asian (SAS) AF: 0.163 AC: 786 AN: 4818

European-Finnish (FIN) AF: 0.0642 AC: 681 AN: 10604

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5246 AN: 67980

Other (OTH) AF: 0.0677 AC: 143 AN: 2112

Alfa AF: 0.0723 Hom.: 1504

Bravo AF: 0.0718

TwinsUK AF: 0.0769 AC: 285

ALSPAC AF: 0.0861 AC: 332

ESP6500AA AF: 0.0640 AC: 282

ESP6500EA AF: 0.0792 AC: 681

ExAC AF: 0.0865 AC: 10501

Asia WGS AF: 0.132 AC: 457 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Mitochondrial complex I deficiency, nuclear type 6 (2)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.38
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.19
Sift	Benign	0.046	D
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.11
MPC		0.57
ClinPred		0.0062	T
GERP RS		3.8
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.059
gMVP		0.30
Mutation Taster		=97/3	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: rs11538340; hg19: chr1-161172233; COSMIC: COSV63487223; COSMIC: COSV63487223;