6-159670528-G-A

Variant names:

• chr6-159670528-G-A
• rs732498
• NM_000636.4:c.*11965C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000636.4(SOD2):​c.*11965C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,046 control chromosomes in the GnomAD database, including 6,046 homozygotes. 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 0.28 (6046 hom., cov: 32)
  • Exomes 𝑓: 0.083 (0 hom.)
• Consequence: SOD2 NM_000636.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.503
• Publications: 18 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD2	NM_000636.4	c.*11965C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000538183.7	NP_000627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD2	ENST00000538183.7	c.*11965C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_000636.4	ENSP00000446252.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42179 AN: 151916 Hom.: 6042 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.100 AC: 1 AN: 10

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.278 AC: 42206 AN: 152034 Hom.: 6046 Cov.: 32 AF XY: 0.285 AC XY: 21194 AN XY: 74324

African (AFR) AF: 0.199 AC: 8233 AN: 41470

American (AMR) AF: 0.304 AC: 4633 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 952 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2090 AN: 5172

South Asian (SAS) AF: 0.344 AC: 1658 AN: 4826

European-Finnish (FIN) AF: 0.370 AC: 3911 AN: 10556

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.293 AC: 19895 AN: 67970

Other (OTH) AF: 0.290 AC: 612 AN: 2108

Alfa AF: 0.288 Hom.: 27583

Bravo AF: 0.268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.57
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs732498; hg19: chr6-160091560;