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]

LOC107984585 (HGNC:):

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: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

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 CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 92657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324370-T-C is described in CliVar as Benign/Likely_benign. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCG	NM_000231.3	c.705T>C	p.Leu235Leu	splice_region_variant, synonymous_variant	Exon 8 of 8	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4	c.705T>C	p.Leu235Leu	splice_region_variant, synonymous_variant	Exon 8 of 8	1	NM_000231.3	ENSP00000218867.3

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

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.705T) is the minor allele. This al lele (T) has been identified in 33% (2878/8600) of European American chromosomes and 60% (2634/4406) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800353) and thus meets c riteria to be classified as benign. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sarcoglycanopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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	-0.58
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;