rs2234694

Variant names:

• chr21-31666552-A-C
• rs2234694
• NM_000454.5:c.239+34A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.14
• Publications: 54 publications found

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: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spastic tetraplegia and axial hypotonia, progressive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000273271 (HGNC:):

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.239+34A>C		intron_variant	Intron 3 of 4	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.239+34A>C		intron_variant	Intron 3 of 4	1	NM_000454.5	ENSP00000270142.7

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5090 AN: 152160 Hom.: 128 Cov.: 32

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

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.: 19 AF XY: 0.0390 AC XY: 25759 AN XY: 660966

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: 11 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: 94 AN: 5500

European-Non Finnish (NFE) AF: 0.0443 AC: 43397 AN: 978836

Other (OTH) AF: 0.0327 AC: 1812 AN: 55466

GnomAD4 genome AF: 0.0334 AC: 5092 AN: 152278 Hom.: 128 Cov.: 32 AF XY: 0.0340 AC XY: 2532 AN XY: 74468

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: 54 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5188

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4830

European-Finnish (FIN) AF: 0.0938 AC: 993 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0474 AC: 3225 AN: 68020

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0374 Hom.: 46

Bravo AF: 0.0271

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.050
DANN	Benign	0.37
PhyloP100		-1.1
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: rs2234694; hg19: chr21-33038865;