Genetic Variant SOD2:p.Lys122Arg (chr6-159685012-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000636.4(SOD2):c.365A>G(p.Lys122Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,606,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SOD2
NM_000636.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.67

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue N6-acetyllysine; alternate (size 0) in uniprot entity SODM_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33345902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD2	NM_000636.4 link	c.365A>G	p.Lys122Arg	missense_variant	Exon 4 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.365A>G	p.Lys122Arg	missense_variant	Exon 4 of 5	1	NM_000636.4	ENSP00000446252.1		P04179-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454484

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;D;.;D;D;D;D;D;D

M_CAP

Benign

0.0068

MetaRNN

Benign

0.33

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

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.2

M;M;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.035

D;D;D;D;D;D;T;D;D

Sift4G

Uncertain

0.040

D;D;T;T;.;.;.;T;T

Polyphen

0.072

B;B;.;.;.;.;.;.;.

Vest4

0.39

MutPred

0.43

Loss of ubiquitination at K122 (P = 0.0244);Loss of ubiquitination at K122 (P = 0.0244);.;.;.;.;.;.;.;

MVP

0.53

MPC

0.46

ClinPred

0.91

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.50

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over