rs11538340

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 480 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5624 hom. )

Consequence

NDUFS2
NM_001377299.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.378

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS2	NM_001377299.1 linkuse as main transcript	c.58C>A	p.Pro20Thr	missense_variant	1/14	ENST00000676972.1	NP_001364228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS2	ENST00000676972.1 linkuse as main transcript	c.58C>A	p.Pro20Thr	missense_variant	1/14		NM_001377299.1	ENSP00000503117	P1	O75306-1

Frequencies

GnomAD3 genomes

AF:

0.0747

AC:

11363

AN:

152046

Hom.:

474

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0854

AC:

20855

AN:

244234

Hom.:

1026

AF XY:

0.0906

AC XY:

12015

AN XY:

132580

show subpopulations

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 SAS exome

AF:

0.168

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.:

AF XY:

0.0857

AC XY:

62253

AN XY:

726090

show subpopulations

Gnomad4 AFR exome

AF:

0.0627

Gnomad4 AMR exome

AF:

0.0773

Gnomad4 ASJ exome

AF:

0.0627

Gnomad4 EAS exome

AF:

0.0867

Gnomad4 SAS exome

AF:

0.169

Gnomad4 FIN exome

AF:

0.0669

Gnomad4 NFE exome

AF:

0.0786

Gnomad4 OTH exome

AF:

0.0868

GnomAD4 genome

AF:

0.0749

AC:

11397

AN:

152164

Hom.:

480

Cov.:

AF XY:

0.0767

AC XY:

5703

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0650

Gnomad4 AMR

AF:

0.0774

Gnomad4 ASJ

AF:

0.0594

Gnomad4 EAS

AF:

0.0703

Gnomad4 SAS

AF:

0.163

Gnomad4 FIN

AF:

0.0642

Gnomad4 NFE

AF:

0.0772

Gnomad4 OTH

AF:

0.0677

Alfa

AF:

0.0708

Hom.:

658

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 27779215) -

Mitochondrial complex 1 deficiency, nuclear type 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Mitochondrial complex I deficiency, nuclear type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.051

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

0.96

P;P;P

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.19

Sift

Benign

0.046

D;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0010

B;.

Vest4

0.11

MPC

0.57

ClinPred

0.0062

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.059

gMVP

0.30

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over