6-159692840-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000636.4(SOD2):c.47T>C(p.Val16Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,610,644 control chromosomes in the GnomAD database, including 197,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.47 (17262 hom., cov: 32)
  • Exomes 𝑓: 0.49 (180259 hom.)
• Consequence: SOD2 NM_000636.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor no assertion criteria provided P:1 B:1 O:1
• Conservation: PhyloP100: 2.20

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.9671322E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD2	NM_000636.4	c.47T>C	p.Val16Ala	missense_variant	2/5	ENST00000538183.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD2	ENST00000538183.7	c.47T>C	p.Val16Ala	missense_variant	2/5	1	NM_000636.4	P1

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71427 AN: 151824 Hom.: 17245 Cov.: 32

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.484 AC: 117709 AN: 243226 Hom.: 29854 AF XY: 0.484 AC XY: 63735 AN XY: 131784

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.519

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.492 AC: 717843 AN: 1458702 Hom.: 180259 Cov.: 48 AF XY: 0.491 AC XY: 356365 AN XY: 725526

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.613

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.519

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.501

Gnomad4 OTH exome AF: 0.476

GnomAD4 genome AF: 0.470 AC: 71475 AN: 151942 Hom.: 17262 Cov.: 32 AF XY: 0.466 AC XY: 34579 AN XY: 74266

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.537

Gnomad4 ASJ AF: 0.519

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.503

Gnomad4 OTH AF: 0.469

Alfa AF: 0.488 Hom.: 30554

Bravo AF: 0.472

TwinsUK AF: 0.490 AC: 1818

ALSPAC AF: 0.477 AC: 1839

ESP6500AA AF: 0.420 AC: 1849

ESP6500EA AF: 0.500 AC: 4303

ExAC AF: 0.476 AC: 57687

Asia WGS AF: 0.349 AC: 1214 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:1 Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Microvascular complications of diabetes, susceptibility to, 6 Pathogenic:1 Other:1

Likely risk allele, no assertion criteria provided	reference population	iDNA Genomics	Jan 01, 2007	- -
risk factor, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -

SUPEROXIDE DISMUTASE 2 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.2
Dann	Benign	0.82
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.000040	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.35	N;N;N;N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.93	T;T;T;T;T;T;T;T
Sift4G	Benign	0.98	T;T;T;T;T;.;.;T
Polyphen		0.024	.;.;.;.;.;.;.;B
Vest4		0.034
MPC		0.56
ClinPred		0.0093	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.24

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

Other links and lift over

dbSNP: rs4880; hg19: chr6-160113872; COSMIC: COSV61622991; COSMIC: COSV61622991;