rs2234694

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000454.5(SOD1):c.239+34A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,465,972 control chromosomes in the GnomAD database, including 1,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 128 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1315 hom. )

Consequence

SOD1
NM_000454.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.14

Publications

54 publications found

Variant links:

Genes affected

SOD1 (HGNC:11179): (superoxide dismutase 1) The protein encoded by this gene binds copper and zinc ions and is one of two isozymes responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic protein, acting as a homodimer to convert naturally-occuring but harmful superoxide radicals to molecular oxygen and hydrogen peroxide. The other isozyme is a mitochondrial protein. In addition, this protein contains an antimicrobial peptide that displays antibacterial, antifungal, and anti-MRSA activity against E. coli, E. faecalis, S. aureus, S. aureus MRSA LPV+, S. agalactiae, and yeast C. krusei. Mutations in this gene have been implicated as causes of familial amyotrophic lateral sclerosis. Rare transcript variants have been reported for this gene. [provided by RefSeq, Jul 2020]

SOD1 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
spastic tetraplegia and axial hypotonia, progressive
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SOD1 links:

ENSG00000273271 (HGNC:):

ENSG00000273271 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 21-31666552-A-C is Benign according to our data. Variant chr21-31666552-A-C is described in ClinVar as Benign. ClinVar VariationId is 256202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0334 (5092/152278) while in subpopulation NFE AF = 0.0474 (3225/68020). AF 95% confidence interval is 0.046. There are 128 homozygotes in GnomAd4. There are 2532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 128 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000454.5. 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
	SOD1	NM_000454.5	MANE Select	c.239+34A>C		intron	N/A	NP_000445.1	P00441

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SOD1	ENST00000270142.11	TSL:1 MANE Select	c.239+34A>C	intron	N/A	ENSP00000270142.7	P00441
SOD1	ENST00000877332.1		c.377+34A>C	intron	N/A	ENSP00000547391.1
SOD1	ENST00000877328.1		c.302+34A>C	intron	N/A	ENSP00000547387.1

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5090

AN:

152160

Hom.:

128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00833

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0938

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0474

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0358

AC:

8654

AN:

241528

AF XY:

0.0360

show subpopulations

Gnomad AFR exome

AF:

0.00831

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.000831

Gnomad FIN exome

AF:

0.0907

Gnomad NFE exome

AF:

0.0486

Gnomad OTH exome

AF:

0.0420

GnomAD4 exome

AF:

0.0398

AC:

52266

AN:

1313694

Hom.:

1315

Cov.:

AF XY:

0.0390

AC XY:

25759

AN XY:

660966

show subpopulations

African (AFR)

AF:

0.00581

AC:

177

AN:

30446

American (AMR)

AF:

0.0179

AC:

787

AN:

44028

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

524

AN:

24974

East Asian (EAS)

AF:

0.000282

AC:

AN:

38940

South Asian (SAS)

AF:

0.0101

AC:

834

AN:

82462

European-Finnish (FIN)

AF:

0.0873

AC:

4630

AN:

53042

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

5500

European-Non Finnish (NFE)

AF:

0.0443

AC:

43397

AN:

978836

Other (OTH)

AF:

0.0327

AC:

1812

AN:

55466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2451

4902

7354

9805

12256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1466

2932

4398

5864

7330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0334

AC:

5092

AN:

152278

Hom.:

128

Cov.:

AF XY:

0.0340

AC XY:

2532

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00830

AC:

345

AN:

41556

American (AMR)

AF:

0.0202

AC:

309

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3470

East Asian (EAS)

AF:

0.00212

AC:

AN:

5188

South Asian (SAS)

AF:

0.0104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0938

AC:

993

AN:

10592

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0474

AC:

3225

AN:

68020

Other (OTH)

AF:

0.0270

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

243

485

728

970

1213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0374

Hom.:

Bravo

AF:

0.0271

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.050

(source)

DANN

Benign

0.37

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over