13-23324370-T-C

Variant names:

• chr13-23324370-T-C
• rs1800353
• NM_000231.3:c.705T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000231.3(SGCG):​c.705T>C​(p.Leu235Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,613,342 control chromosomes in the GnomAD database, including 358,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29603 hom., cov: 33)
  • Exomes 𝑓: 0.67 (328501 hom.)
• Consequence: SGCG NM_000231.3 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0490
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 13-23324370-T-C is Benign according to our data. Variant chr13-23324370-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.733 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.705T>C	p.Leu235Leu	splice_region synonymous	Exon 8 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.759T>C	p.Leu253Leu	splice_region synonymous	Exon 8 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.705T>C	p.Leu235Leu	splice_region synonymous	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.705T>C	p.Leu235Leu	splice_region synonymous	Exon 8 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.885T>C	p.Leu295Leu	splice_region synonymous	Exon 9 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.705T>C	p.Leu235Leu	splice_region synonymous	Exon 9 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92598 AN: 152034 Hom.: 29582 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.686 AC: 171986 AN: 250680 AF XY: 0.689

Gnomad AFR exome AF: 0.393

Gnomad AMR exome AF: 0.811

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.662

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.667 AC: 974972 AN: 1461188 Hom.: 328501 Cov.: 47 AF XY: 0.669 AC XY: 486485 AN XY: 726922

African (AFR) AF: 0.382 AC: 12787 AN: 33454

American (AMR) AF: 0.805 AC: 35979 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20430 AN: 26130

East Asian (EAS) AF: 0.773 AC: 30703 AN: 39698

South Asian (SAS) AF: 0.717 AC: 61823 AN: 86236

European-Finnish (FIN) AF: 0.662 AC: 35335 AN: 53386

Middle Eastern (MID) AF: 0.703 AC: 4055 AN: 5768

European-Non Finnish (NFE) AF: 0.660 AC: 733863 AN: 1111436

Other (OTH) AF: 0.663 AC: 39997 AN: 60366

GnomAD4 genome AF: 0.609 AC: 92653 AN: 152154 Hom.: 29603 Cov.: 33 AF XY: 0.618 AC XY: 45960 AN XY: 74372

African (AFR) AF: 0.404 AC: 16745 AN: 41490

American (AMR) AF: 0.737 AC: 11279 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2712 AN: 3468

East Asian (EAS) AF: 0.753 AC: 3890 AN: 5168

South Asian (SAS) AF: 0.729 AC: 3512 AN: 4816

European-Finnish (FIN) AF: 0.674 AC: 7136 AN: 10592

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45110 AN: 68012

Other (OTH) AF: 0.650 AC: 1375 AN: 2114

Alfa AF: 0.637 Hom.: 25204

Bravo AF: 0.606

Asia WGS AF: 0.746 AC: 2596 AN: 3478

EpiCase AF: 0.666

EpiControl AF: 0.673

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Autosomal recessive limb-girdle muscular dystrophy type 2C (4)
-	-	2	not provided (2)
-	-	1	Charlevoix-Saguenay spastic ataxia (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.68
PhyloP100		0.049
Mutation Taster		=96/4	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: rs1800353; hg19: chr13-23898509;