6-159682514-T-A

Variant names:

• chr6-159682514-T-A
• NM_000636.4:c.648A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000636.4(SOD2):​c.648A>T​(p.Arg216Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SOD2 NM_000636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72
• Publications: 0 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):

• microvascular complications of diabetes, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• cardiomyopathy

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

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD2	NM_000636.4	MANE Select	c.648A>T	p.Arg216Ser	missense	Exon 5 of 5	NP_000627.2	P04179-1
	SOD2	NM_001024465.3		c.648A>T	p.Arg216Ser	missense	Exon 5 of 6	NP_001019636.1	P04179-1
	SOD2	NM_001024466.3		c.531A>T	p.Arg177Ser	missense	Exon 4 of 5	NP_001019637.1	P04179-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD2	ENST00000538183.7	TSL:1 MANE Select	c.648A>T	p.Arg216Ser	missense	Exon 5 of 5	ENSP00000446252.1	P04179-1
	SOD2	ENST00000367055.8	TSL:1	c.648A>T	p.Arg216Ser	missense	Exon 5 of 6	ENSP00000356022.4	P04179-1
	SOD2	ENST00000881541.1		c.645A>T	p.Arg215Ser	missense	Exon 5 of 5	ENSP00000551600.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.76		Loss of MoRF binding (P = 0.034)
MVP		0.81
MPC		1.4
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.75
gMVP		0.78
Mutation Taster		=8/92	disease causing

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

Other links and lift over

hg19: chr6-160103546;