rs5746096

Positions:

• chr6-159692858-C-A
• chr6-159692858-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000636.4(SOD2):​c.29G>T​(p.Ser10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,605,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: SOD2 NM_000636.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75

Genes affected

SOD2 (HGNC:11180): (superoxide dismutase 2) This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 1. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005635321).
• BS2: High AC in GnomAd4 at 250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD2	NM_000636.4	c.29G>T	p.Ser10Ile	missense_variant	2/5	ENST00000538183.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD2	ENST00000538183.7	c.29G>T	p.Ser10Ile	missense_variant	2/5	1	NM_000636.4	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152218 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000949 AC: 219 AN: 230756 Hom.: 0 AF XY: 0.000894 AC XY: 112 AN XY: 125254

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000918

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000439

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000554 AC: 805 AN: 1453440 Hom.: 1 Cov.: 32 AF XY: 0.000556 AC XY: 402 AN XY: 722686

Gnomad4 AFR exome AF: 0.00372

Gnomad4 AMR exome AF: 0.00234

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000971

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000270

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152336 Hom.: 0 Cov.: 31 AF XY: 0.00176 AC XY: 131 AN XY: 74504

Gnomad4 AFR AF: 0.00317

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000723 Hom.: 6

Bravo AF: 0.00219

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000800 AC: 97

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;.;.;.;T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.029	D;D;D;T;D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;T;T;.;.;D
Polyphen		0.072	B;B;.;.;.;.;.;D
Vest4		0.30
MVP		0.54
MPC		0.56
ClinPred		0.026	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.51

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: rs5746096; hg19: chr6-160113890;