rs35086265

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 14/20 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

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.702
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 214787.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}.
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 Mitochondrial gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NDUFS2NM_001377299.1 linkc.968G>A p.Arg323Gln missense_variant Exon 9 of 14 ENST00000676972.1 NP_001364228.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDUFS2ENST00000676972.1 linkc.968G>A p.Arg323Gln missense_variant Exon 9 of 14 NM_001377299.1 ENSP00000503117.1 O75306-1

Frequencies

GnomAD3 genomes
AF:
0.00463
AC:
704
AN:
152042
Hom.:
5
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00481
AC:
1209
AN:
251458
Hom.:
6
AF XY:
0.00482
AC XY:
655
AN XY:
135912
show subpopulations
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 SAS exome
AF:
0.00376
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000687
Gnomad4 AMR exome
AF:
0.00519
Gnomad4 ASJ exome
AF:
0.00490
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00342
Gnomad4 FIN exome
AF:
0.0146
Gnomad4 NFE exome
AF:
0.00522
Gnomad4 OTH exome
AF:
0.00475
GnomAD4 genome
AF:
0.00463
AC:
704
AN:
152160
Hom.:
5
Cov.:
32
AF XY:
0.00539
AC XY:
401
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.00104
Gnomad4 AMR
AF:
0.00943
Gnomad4 ASJ
AF:
0.00576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00333
Gnomad4 FIN
AF:
0.0173
Gnomad4 NFE
AF:
0.00426
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00430
Hom.:
2
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

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 18, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NDUFS2: BP4, BS2 -

Mitochondrial complex 1 deficiency, nuclear type 6 Benign:2
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 15, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1
Dec 21, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

NDUFS2-related disorder Benign:1
Jun 21, 2024
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;D
MetaRNN
Benign
0.013
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.83
L;L
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.99
N;N
REVEL
Uncertain
0.53
Sift
Benign
0.12
T;T
Sift4G
Benign
0.17
T;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

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs35086265; hg19: chr1-161180482; COSMIC: COSV99248123; COSMIC: COSV99248123; API