6-159685031-C-T

Variant names:

• chr6-159685031-C-T
• NM_000636.4:c.346G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000636.4(SOD2):​c.346G>A​(p.Glu116Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000007 in 1,429,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SOD2 NM_000636.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD2	NM_000636.4	c.346G>A	p.Glu116Lys	missense_variant, splice_region_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	c.346G>A	p.Glu116Lys	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_000636.4	ENSP00000446252.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429492 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.;T;T;T;T;.
Eigen	Benign	-0.0051
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	D;D;D;D;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;.;.;.;T;T
Polyphen		0.0010	B;B;.;.;.;.;.;.;.
Vest4		0.64
MutPred		0.57		Gain of ubiquitination at E116 (P = 0.0121);Gain of ubiquitination at E116 (P = 0.0121);.;.;.;.;.;.;.;
MVP		0.62
MPC		0.52
ClinPred		0.93	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-160106063; COSMIC: COSV100496573;