rs35086265

chr1-161210692-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.702

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]

ACMG classification

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: {Uncertain_significance=1, Benign=2, Likely_benign=4}.
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS2	NM_001377299.1	c.968G>A	p.Arg323Gln	missense_variant	9/14	ENST00000676972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS2	ENST00000676972.1	c.968G>A	p.Arg323Gln	missense_variant	9/14		NM_001377299.1	P1

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

GnomAD3 exomes AF: 0.00481 AC: 1209 AN: 251458 Hom.: 6 AF XY: 0.00482 AC XY: 655 AN XY: 135912

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

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

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:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NDUFS2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Mitochondrial complex 1 deficiency, nuclear type 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2017

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. -

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
MutationTaster	Benign	1.0	N;N;N
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

Other links and lift over

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