rs147820869

chr13-23324497-G-Achr13-23324497-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a chain Gamma-sarcoglycan (size 290) in uniprot entity SGCG_HUMAN there are 38 pathogenic changes around while only 8 benign (83%) in NM_000231.3
• 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 id is 285833.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCG	NM_000231.3	c.832G>A	p.Gly278Ser	missense_variant	8/8	ENST00000218867.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCG	ENST00000218867.4	c.832G>A	p.Gly278Ser	missense_variant	8/8	1	NM_000231.3	P1

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

GnomAD3 exomes AF: 0.000776 AC: 195 AN: 251336 Hom.: 0 AF XY: 0.000662 AC XY: 90 AN XY: 135852

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.000812

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

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000664 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2020	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 19, 2020	- -

Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sarcoglycanopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs147820869; hg19: chr13-23898636;