rs9510701

Positions:

• chr13-23324554-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000231.3(SGCG):​c.*13C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,606,276 control chromosomes in the GnomAD database, including 1,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (289 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1604 hom.)
• Consequence: SGCG NM_000231.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.37

Genes affected

SGCG (HGNC:10809): (sarcoglycan gamma) This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-23324554-C-T is Benign according to our data. Variant chr13-23324554-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324554-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCG	NM_000231.3	c.*13C>T		3_prime_UTR_variant	8/8	ENST00000218867.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCG	ENST00000218867.4	c.*13C>T		3_prime_UTR_variant	8/8	1	NM_000231.3	P1

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8109 AN: 152058 Hom.: 288 Cov.: 32

Gnomad AFR AF: 0.0860

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0384

Gnomad OTH AF: 0.0579

GnomAD3 exomes AF: 0.0416 AC: 10321 AN: 248348 Hom.: 349 AF XY: 0.0401 AC XY: 5388 AN XY: 134384

Gnomad AFR exome AF: 0.0891

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.129

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0375

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0422 AC: 61377 AN: 1454100 Hom.: 1604 Cov.: 32 AF XY: 0.0411 AC XY: 29746 AN XY: 723666

Gnomad4 AFR exome AF: 0.0948

Gnomad4 AMR exome AF: 0.0174

Gnomad4 ASJ exome AF: 0.0433

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.0417

Gnomad4 OTH exome AF: 0.0492

GnomAD4 genome AF: 0.0534 AC: 8121 AN: 152176 Hom.: 289 Cov.: 32 AF XY: 0.0521 AC XY: 3873 AN XY: 74372

Gnomad4 AFR AF: 0.0862

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0383

Gnomad4 OTH AF: 0.0568

Alfa AF: 0.0449 Hom.: 55

Bravo AF: 0.0575

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.*13C>T in exon 8 of SGCG: This variant is not expected to have clinical signif icance because it has been identified in 8.5% (373/4406) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs9510701). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sarcoglycanopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charlevoix-Saguenay spastic ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.59

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: rs9510701; hg19: chr13-23898693;