rs2234694

chr21-31666552-A-C

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 128 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD1	NM_000454.5	c.239+34A>C		intron_variant		ENST00000270142.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD1	ENST00000270142.11	c.239+34A>C		intron_variant		1	NM_000454.5	P1
SOD1	ENST00000389995.4	c.182+34A>C		intron_variant		3
SOD1	ENST00000470944.1	n.1167+34A>C		intron_variant, non_coding_transcript_variant		2
SOD1	ENST00000476106.5	n.502+34A>C		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.0358 AC: 8654 AN: 241528 Hom.: 250 AF XY: 0.0360 AC XY: 4696 AN XY: 130346

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 SAS exome AF: 0.00968

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

Gnomad4 AFR exome AF: 0.00581

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.000282

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0873

Gnomad4 NFE exome AF: 0.0443

Gnomad4 OTH exome AF: 0.0327

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

Gnomad4 AFR AF: 0.00830

Gnomad4 AMR AF: 0.0202

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0938

Gnomad4 NFE AF: 0.0474

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0409 Hom.: 30

Bravo AF: 0.0271

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.050
Dann	Benign	0.37

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

LitVar

Other links and lift over

dbSNP: rs2234694; hg19: chr21-33038865;