Genetic Variant SOD2:p.Ser10Ile (chr6-159692858-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

SOD2
NM_000636.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.75

Publications

8 publications found

Variant links:

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]

SOD2 Gene-Disease associations (from GenCC):

cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SOD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005635321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD2	NM_000636.4 link	c.29G>T	p.Ser10Ile	missense_variant	Exon 2 of 5	ENST00000538183.7	NP_000627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD2	ENST00000538183.7 link	c.29G>T	p.Ser10Ile	missense_variant	Exon 2 of 5	1	NM_000636.4	ENSP00000446252.1		P04179-1

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

250

AN:

152218

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000949

AC:

219

AN:

230756

AF XY:

0.000894

show subpopulations

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 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.:

Cov.:

AF XY:

0.000556

AC XY:

402

AN XY:

722686

show subpopulations

African (AFR)

AF:

0.00372

AC:

124

AN:

33332

American (AMR)

AF:

0.00234

AC:

102

AN:

43540

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.000971

AC:

AN:

85442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51164

Middle Eastern (MID)

AF:

0.00355

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.000270

AC:

299

AN:

1108880

Other (OTH)

AF:

0.00163

AC:

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152336

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00317

AC:

132

AN:

41576

American (AMR)

AF:

0.00483

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00219

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000800

AC:

Asia WGS

AF:

0.000866

AC:

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

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

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

LIST_S2

Benign

0.74

.;T;.;T;T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0056

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;L;L;L;.;.;.

PhyloP100

1.7

PrimateAI

Uncertain

0.65

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

GERP RS

3.0

PromoterAI

0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.51

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over