rs9580603

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000231.3(SGCG):c.703-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,802 control chromosomes in the GnomAD database, including 595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene SGCG is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.037 ( 302 hom., cov: 34)

Exomes 𝑓: 0.0080 ( 293 hom. )

Consequence

SGCG
NM_000231.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.108

Publications

4 publications found

Variant links:

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]

SGCG links:

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

SACS links:

LOC107984585 (HGNC:):

LOC107984585 links:

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ACMG classification

Specifications for SGCG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 13-23324350-T-C is Benign according to our data. Variant chr13-23324350-T-C is described in ClinVar as Benign. ClinVar VariationId is 92656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SGCG	NM_000231.3	MANE Select	c.703-18T>C	intron	N/A	NP_000222.2	Q13326
SGCG	NM_001378244.1		c.757-18T>C	intron	N/A	NP_001365173.1
SGCG	NM_001378245.1		c.703-18T>C	intron	N/A	NP_001365174.1	Q13326

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SGCG	ENST00000218867.4	TSL:1 MANE Select	c.703-18T>C	intron	N/A	ENSP00000218867.3	Q13326
SACS	ENST00000682775.1		c.2186-12235A>G	intron	N/A	ENSP00000508399.1	A0A804HLK7
SACS	ENST00000683210.1		c.2185+29435A>G	intron	N/A	ENSP00000506739.1	A0A804HHS6

Frequencies

GnomAD3 genomes

AF:

0.0374

AC:

5686

AN:

152200

Hom.:

297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00962

Gnomad SAS

AF:

0.00744

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.00442

Gnomad OTH

AF:

0.0387

GnomAD2 exomes

AF:

0.0144

AC:

3610

AN:

250534

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0188

Gnomad EAS exome

AF:

0.00788

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.00804

AC:

11744

AN:

1461484

Hom.:

293

Cov.:

AF XY:

0.00789

AC XY:

5736

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.114

AC:

3815

AN:

33422

American (AMR)

AF:

0.0114

AC:

510

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

483

AN:

26136

East Asian (EAS)

AF:

0.0127

AC:

506

AN:

39696

South Asian (SAS)

AF:

0.0108

AC:

930

AN:

86246

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.0398

AC:

229

AN:

5760

European-Non Finnish (NFE)

AF:

0.00393

AC:

4365

AN:

1111762

Other (OTH)

AF:

0.0149

AC:

899

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

527

1055

1582

2110

2637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0375

AC:

5710

AN:

152318

Hom.:

302

Cov.:

AF XY:

0.0365

AC XY:

2719

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.117

AC:

4858

AN:

41562

American (AMR)

AF:

0.0190

AC:

290

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00965

AC:

AN:

5184

South Asian (SAS)

AF:

0.00766

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00443

AC:

301

AN:

68018

Other (OTH)

AF:

0.0383

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

272

545

817

1090

1362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0265

Hom.:

Bravo

AF:

0.0427

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Autosomal recessive limb-girdle muscular dystrophy type 2C (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.8

(source)

DANN

Benign

0.56

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over