rs9510701

Variant names:

• chr13-23324554-C-T
• rs9510701
• NM_000231.3:c.*13C>T

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: -1.37
• Publications: 4 publications found

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]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia, G2P, Myriad Women’s Health, Orphanet

LOC107984585 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000231.3. 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
	SGCG	NM_000231.3	MANE Select	c.*13C>T		3_prime_UTR	Exon 8 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.*13C>T		3_prime_UTR	Exon 8 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.*13C>T		3_prime_UTR	Exon 9 of 9	NP_001365174.1	Q13326

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	ENST00000218867.4	TSL:1 MANE Select	c.*13C>T		3_prime_UTR	Exon 8 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.*13C>T		3_prime_UTR	Exon 9 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.*13C>T		3_prime_UTR	Exon 9 of 9	ENSP00000546423.1

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

GnomAD2 exomes AF: 0.0416 AC: 10321 AN: 248348 AF XY: 0.0401

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 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

African (AFR) AF: 0.0948 AC: 3166 AN: 33386

American (AMR) AF: 0.0174 AC: 779 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 1130 AN: 26118

East Asian (EAS) AF: 0.100 AC: 3981 AN: 39666

South Asian (SAS) AF: 0.0155 AC: 1339 AN: 86110

European-Finnish (FIN) AF: 0.0313 AC: 1526 AN: 48774

Middle Eastern (MID) AF: 0.0271 AC: 116 AN: 4288

European-Non Finnish (NFE) AF: 0.0417 AC: 46379 AN: 1110884

Other (OTH) AF: 0.0492 AC: 2961 AN: 60158

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

African (AFR) AF: 0.0862 AC: 3579 AN: 41500

American (AMR) AF: 0.0341 AC: 522 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3472

East Asian (EAS) AF: 0.126 AC: 651 AN: 5154

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4818

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0383 AC: 2608 AN: 68012

Other (OTH) AF: 0.0568 AC: 120 AN: 2112

Alfa AF: 0.0449 Hom.: 55

Bravo AF: 0.0575

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2C (1)
-	-	1	Charlevoix-Saguenay spastic ataxia (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	not provided (1)
-	-	1	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.59
PhyloP100		-1.4
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: rs9510701; hg19: chr13-23898693;