rs147820869

Variant names:

• chr13-23324497-G-A
• rs147820869
• NM_000231.3:c.832G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-23324497-G-A
• chr13-23324497-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000231.3(SGCG):​c.832G>A​(p.Gly278Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,298 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G278D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: SGCG NM_000231.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 7.26
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009368837).
• BP6: Variant 13-23324497-G-A is Benign according to our data. Variant chr13-23324497-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285833.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.832G>A	p.Gly278Ser	missense	Exon 8 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.886G>A	p.Gly296Ser	missense	Exon 8 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.832G>A	p.Gly278Ser	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.832G>A	p.Gly278Ser	missense	Exon 8 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.1012G>A	p.Gly338Ser	missense	Exon 9 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.832G>A	p.Gly278Ser	missense	Exon 9 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000776 AC: 195 AN: 251336 AF XY: 0.000662

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000309 AC: 452 AN: 1461132 Hom.: 2 Cov.: 52 AF XY: 0.000316 AC XY: 230 AN XY: 726872

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.000581 AC: 26 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00983 AC: 257 AN: 26136

East Asian (EAS) AF: 0.000856 AC: 34 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.000566 AC: 3 AN: 5304

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1111996

Other (OTH) AF: 0.000812 AC: 49 AN: 60334

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74378

African (AFR) AF: 0.0000482 AC: 2 AN: 41492

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000630 Hom.: 0

Bravo AF: 0.000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2C (2)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0094	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.61
Sift	Benign	0.068	T
Sift4G	Uncertain	0.046	D
Polyphen		0.97	D
Vest4		0.15
MVP		0.94
MPC		0.14
ClinPred		0.097	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.56
Mutation Taster		=61/39	polymorphism

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: rs147820869; hg19: chr13-23898636;