13-23324525-A-G

Variant names:

• chr13-23324525-A-G
• rs1800354
• NM_000231.3:c.860A>G

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.860A>G​(p.Asn287Ser) variant causes a missense change. The variant allele was found at a frequency of 0.873 in 1,611,402 control chromosomes in the GnomAD database, including 615,354 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N287T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.84 (54415 hom., cov: 29)
  • Exomes 𝑓: 0.88 (560939 hom.)
• Consequence: SGCG NM_000231.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.11
• Publications: 33 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 (MetaRNN=6.4305704E-7).
• BP6: Variant 13-23324525-A-G is Benign according to our data. Variant chr13-23324525-A-G is described in ClinVar as Benign. ClinVar VariationId is 167681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.860A>G	p.Asn287Ser	missense	Exon 8 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.914A>G	p.Asn305Ser	missense	Exon 8 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.860A>G	p.Asn287Ser	missense	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.860A>G	p.Asn287Ser	missense	Exon 8 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.1040A>G	p.Asn347Ser	missense	Exon 9 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.860A>G	p.Asn287Ser	missense	Exon 9 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128032 AN: 151806 Hom.: 54383 Cov.: 29

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.865

GnomAD2 exomes AF: 0.886 AC: 222275 AN: 250754 AF XY: 0.888

Gnomad AFR exome AF: 0.739

Gnomad AMR exome AF: 0.935

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.883

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.883

GnomAD4 exome AF: 0.876 AC: 1278246 AN: 1459478 Hom.: 560939 Cov.: 49 AF XY: 0.877 AC XY: 636522 AN XY: 726134

African (AFR) AF: 0.732 AC: 24465 AN: 33426

American (AMR) AF: 0.931 AC: 41616 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 24003 AN: 26134

East Asian (EAS) AF: 0.999 AC: 39678 AN: 39698

South Asian (SAS) AF: 0.912 AC: 78559 AN: 86182

European-Finnish (FIN) AF: 0.882 AC: 46336 AN: 52556

Middle Eastern (MID) AF: 0.857 AC: 4039 AN: 4712

European-Non Finnish (NFE) AF: 0.870 AC: 966728 AN: 1111790

Other (OTH) AF: 0.877 AC: 52822 AN: 60260

GnomAD4 genome AF: 0.843 AC: 128121 AN: 151924 Hom.: 54415 Cov.: 29 AF XY: 0.849 AC XY: 63055 AN XY: 74248

African (AFR) AF: 0.740 AC: 30590 AN: 41346

American (AMR) AF: 0.899 AC: 13749 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3175 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5131 AN: 5136

South Asian (SAS) AF: 0.921 AC: 4426 AN: 4808

European-Finnish (FIN) AF: 0.890 AC: 9410 AN: 10576

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58816 AN: 67984

Other (OTH) AF: 0.867 AC: 1825 AN: 2106

Alfa AF: 0.862 Hom.: 129252

Bravo AF: 0.842

TwinsUK AF: 0.866 AC: 3212

ALSPAC AF: 0.876 AC: 3375

ESP6500AA AF: 0.731 AC: 3221

ESP6500EA AF: 0.867 AC: 7458

ExAC AF: 0.882 AC: 107033

Asia WGS AF: 0.944 AC: 3283 AN: 3478

EpiCase AF: 0.861

EpiControl AF: 0.864

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Autosomal recessive limb-girdle muscular dystrophy type 2C (5)
-	-	5	not specified (5)
-	-	1	Charlevoix-Saguenay spastic ataxia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.57
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	6.4e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.2	N
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.056
ClinPred		0.0020	T
GERP RS		5.4
Varity_R		0.038
gMVP		0.45
Mutation Taster		=99/1	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: rs1800354; hg19: chr13-23898664; COSMIC: COSV54566326; COSMIC: COSV54566326;