13-23324525-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 14/20 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:11
• Conservation: PhyloP100: 4.11

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 Benign. Variant got -18 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=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 id is 167681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324525-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCG	NM_000231.3	c.860A>G	p.Asn287Ser	missense_variant	8/8	ENST00000218867.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCG	ENST00000218867.4	c.860A>G	p.Asn287Ser	missense_variant	8/8	1	NM_000231.3	P1

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

GnomAD3 exomes AF: 0.886 AC: 222275 AN: 250754 Hom.: 98962 AF XY: 0.888 AC XY: 120406 AN XY: 135572

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 SAS exome AF: 0.913

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

Gnomad4 AFR exome AF: 0.732

Gnomad4 AMR exome AF: 0.931

Gnomad4 ASJ exome AF: 0.918

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.912

Gnomad4 FIN exome AF: 0.882

Gnomad4 NFE exome AF: 0.870

Gnomad4 OTH exome AF: 0.877

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

Gnomad4 AFR AF: 0.740

Gnomad4 AMR AF: 0.899

Gnomad4 ASJ AF: 0.916

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.921

Gnomad4 FIN AF: 0.890

Gnomad4 NFE AF: 0.865

Gnomad4 OTH AF: 0.867

Alfa AF: 0.868 Hom.: 93145

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

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.860A) is the minor allele. This al lele (A) has been identified in 13% (1142/8600) of European American chromosomes and 27% (1185/4406) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800354) and thus meets c riteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Charlevoix-Saguenay spastic ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P;P;P
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

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: rs1800354; hg19: chr13-23898664; COSMIC: COSV54566326; COSMIC: COSV54566326;